ClinVar Genomic variation as it relates to human health
NM_001384474.1(LOXHD1):c.4480C>T (p.Arg1494Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001384474.1(LOXHD1):c.4480C>T (p.Arg1494Ter)
Variation ID: 178396 Accession: VCV000178396.63
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.1 18: 46529227 (GRCh38) [ NCBI UCSC ] 18: 44109190 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 9, 2016 May 12, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001384474.1:c.4480C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001371403.1:p.Arg1494Ter nonsense NM_001145472.3:c.1147C>T NP_001138944.1:p.Arg383Ter nonsense NM_001308013.2:c.859C>T NP_001294942.1:p.Arg287Ter nonsense NM_144612.7:c.4480C>T NP_653213.6:p.Arg1494Ter nonsense NC_000018.10:g.46529227G>A NC_000018.9:g.44109190G>A NG_016646.2:g.132807C>T - Protein change
- R1494*, R383*, R287*
- Other names
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- Canonical SPDI
- NC_000018.10:46529226:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00058
Trans-Omics for Precision Medicine (TOPMed) 0.00059
The Genome Aggregation Database (gnomAD) 0.00069
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00131
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOXHD1 | - | - |
GRCh38 GRCh37 |
2493 | 2536 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Aug 8, 2018 | RCV000155144.7 | |
Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000256002.33 | |
Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2023 | RCV000381729.28 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 26, 2023 | RCV001544522.3 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000408722.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The LOXHD1 c.4480C>T (p.Arg1494Ter) variant is a stop-gained variant that has been reported in a total of three studies in which it is found in … (more)
The LOXHD1 c.4480C>T (p.Arg1494Ter) variant is a stop-gained variant that has been reported in a total of three studies in which it is found in a homozygous state in two siblings and in a compound heterozygous state in three individuals (including two siblings), all with nonsyndromic hearing loss. The variant has also been reported in a heterozygous state in at least four unaffected individuals (Diaz-Horta et al. 2012; Eppsteiner et al. 2012; Mori et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of stop-gained variants and supporting evidence, the p.Arg1494Ter variant is classified as likely pathogenic for recessively inherited nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Deafness, autosomal recessive 77
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000923732.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Number of individuals with the variant: 1
Sex: female
Geographic origin: Iran
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Pathogenic
(Mar 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893497.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004100192.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
Variant summary: LOXHD1 c.4480C>T (p.Arg1494X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly … (more)
Variant summary: LOXHD1 c.4480C>T (p.Arg1494X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00061 in 158746 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in LOXHD1 causing Nonsyndromic Hearing Loss And Deafness, Type 77 (0.00061 vs 0.0011), allowing no conclusion about variant significance. c.4480C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Nonsyndromic Hearing Loss And Deafness, Type 77 and has been found to segregate with this phenotype in affected families (e.g. Diaz-Horta_2012, Maekawa_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23226338, 31547530). Thirteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Mar 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004175864.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The stop gain c.4480C>T (p.Arg1494Ter) variant in LOXHD1 gene has been reported in homozygous, compound heterozygous and heterozygous state in individuals affected with deafness and … (more)
The stop gain c.4480C>T (p.Arg1494Ter) variant in LOXHD1 gene has been reported in homozygous, compound heterozygous and heterozygous state in individuals affected with deafness and non syndromic hearing loss (Mori K, et. al., 2015). It has also been observed to segregate with disease in related individuals. The p.Arg1494Ter variant has allele frequency 0.07% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The nucleotide change c.4480C>T in LOXHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in LOXHD1 gene have been previously reported to be pathogenic (Mori K, et. al., 2015; Edvardson S, et. al., 2011). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002017172.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000964218.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1494*) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg1494*) in the LOXHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LOXHD1 are known to be pathogenic (PMID: 19732867, 21465660, 25792669). This variant is present in population databases (rs201587138, gnomAD 0.1%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individual(s) with deafness and non syndromic hearing loss (PMID: 22975204, 23226338, 25792669). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178396). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Sep 12, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000345465.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 4
Sex: mixed
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Pathogenic
(Aug 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rare genetic deafness
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000204830.4
First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018 |
Comment:
The p.Arg1494X variant in LOXHD1 has been reported in a homozygous state in two siblings with hearing loss from a consanguineous family (Diaz-Horta 2012) and … (more)
The p.Arg1494X variant in LOXHD1 has been reported in a homozygous state in two siblings with hearing loss from a consanguineous family (Diaz-Horta 2012) and in the compound heterozygous state with a second variant in LOXHD1 in two siblings in another family (Mori 2015). It has also been identified by our laboratory in three individuals with hearing loss, including one homozygote and two with a se cond LOXHD1 variant. This variant has been identified in 0.1% (88/73010) of Euro pean chromosomes by the Genome Aggregation Database (gnomAD, http://exac.broadin stitute.org; dbSNP rs201587138). This frequency is low enough to be consistent w ith autosomal recessive carrier frequency for hearing loss in the general popula tion. This nonsense variant leads to a premature termination codon at position 1 494, which is predicted to lead to a truncated or absent protein. Homozygous los s of function of the LOXHD1 gene is an established disease mechanism for hearing loss. In summary, this variant meets criteria to be classified as pathogenic in an autosomal recessive manner based upon the predicted impact of the variant, b iallelic states in multiple affected individuals, and segregation evidence. ACMG /AMP Criteria applied: PVS1; PM3_Strong. (less)
Number of individuals with the variant: 10
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Pathogenic
(Jul 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Nonsyndromic genetic hearing loss
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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INGEBI, INGEBI / CONICET
Accession: SCV001763595.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.4480 C>T (p.Arg1494*) in LOXHD1 gene is predicted to cause a premature stop … (more)
Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.4480 C>T (p.Arg1494*) in LOXHD1 gene is predicted to cause a premature stop codon in biologically-relevant-exon 29/40 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism, NMD is predcited to occur, (PVS1). The variant filter allele frequency is 0.08% (from non-european alleles in gnomAD with 95%CI) applying to BS1_Supporting. The c.4480 C>T variant has been identified in trans with two different pathogenic/likley pathogenic in patients with diverse severity of hearing loss (PMID: 22975204 and PMID: 25792669). Besides, it was detected in homozygous state in two different probands (PMID: 23226338 and this study) meeting PM3_Strong. In addition to this, this variant segregated in two different family cases with two sibling with non-syndromic hearing loss, applying to PP1_Moderate (PMID: 23226338, 25792669). Taking all the information together together :PVS1, BS1_Supporting, PM3_Strong, PP1_Moderate, c.4480C>T is classified as Pathogenic for autosomal recessive non-syndromic hearing loss. (less)
Clinical Features:
Congenital profound bilateral hearing loss (present)
Family history: no
Sex: male
Ethnicity/Population group: Caucasian
Geographic origin: Argentina
Tissue: blood
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Pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 77
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557229.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 29 of 40). (P) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (122 heterozygotes, 1 homozygote). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Other variants predicted to cause NMD have been reported in ClinVar as pathogenic in individuals with autosomal recessive deafness. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has been previously reported as pathogenic in patients with autosomal recessive deafness (ClinVar, PMID: 23226338, 25792669). (P) 1205 - Variant is maternally inherited. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
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Pathogenic
(Nov 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000322108.10
First in ClinVar: Oct 09, 2016 Last updated: Dec 03, 2022 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 22975204, 25792669, 26973026, 28984810, 31980526, 31589614, 33297549, 29676012, 26969326, 23226338, 29907799, 30622556, 34997062, 32860223) (less)
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Pathogenic
(Apr 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245850.21
First in ClinVar: May 09, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 3
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972574.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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Likely pathogenic
(Oct 26, 2015)
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no assertion criteria provided
Method: research
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: yes
Allele origin:
germline
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Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536821.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive deafness type 77
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460014.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001953942.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Autosomal recessive nonsyndromic hearing loss 77
Affected status: unknown
Allele origin:
unknown
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GenomeConnect, ClinGen
Accession: SCV000986911.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as pathogenic and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more)
Variant interpretted as pathogenic and reported on 07/21/2017 by GTR ID Shodair Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Premature birth (present) , Abnormality of eye movement (present) , Sensorineural hearing loss (present) , Tinnitus (present) , Cerebral palsy (present) , Hypertonia (present)
Age: 40-49 years
Sex: female
Testing laboratory: Genetics Laboratory,Shodair Children's Hospital
Date variant was reported to submitter: 2017-07-21
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Mutational Spectrum and Clinical Features of Patients with LOXHD1 Variants Identified in an 8074 Hearing Loss Patient Cohort. | Maekawa K | Genes | 2019 | PMID: 31547530 |
Mutations in LOXHD1 gene cause various types and severities of hearing loss. | Mori K | The Annals of otology, rhinology, and laryngology | 2015 | PMID: 25792669 |
Whole-exome sequencing efficiently detects rare mutations in autosomal recessive nonsyndromic hearing loss. | Diaz-Horta O | PloS one | 2012 | PMID: 23226338 |
Prediction of cochlear implant performance by genetic mutation: the spiral ganglion hypothesis. | Eppsteiner RW | Hearing research | 2012 | PMID: 22975204 |
A deleterious mutation in the LOXHD1 gene causes autosomal recessive hearing loss in Ashkenazi Jews. | Edvardson S | American journal of medical genetics. Part A | 2011 | PMID: 21465660 |
Mutations in LOXHD1, an evolutionarily conserved stereociliary protein, disrupt hair cell function in mice and cause progressive hearing loss in humans. | Grillet N | American journal of human genetics | 2009 | PMID: 19732867 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=LOXHD1 | - | - | - | - |
Text-mined citations for rs201587138 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.