ClinVar Genomic variation as it relates to human health
NM_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)
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_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)
Variation ID: 846771 Accession: VCV000846771.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.1 3: 42688963 (GRCh38) [ NCBI UCSC ] 3: 42730455 (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 Apr 15, 2020 Feb 20, 2024 Nov 28, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_152393.4:c.1516A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_689606.2:p.Thr506Pro missense NC_000003.12:g.42688963A>C NC_000003.11:g.42730455A>C NG_033035.1:g.8445A>C - Protein change
- T506P
- Other names
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- Canonical SPDI
- NC_000003.12:42688962:A:C
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- Links
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
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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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KLHL40 | - | - |
GRCh38 GRCh37 |
495 | 502 |
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 (5) |
criteria provided, multiple submitters, no conflicts
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Nov 28, 2022 | RCV001050162.11 |
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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Pathogenic
(Feb 01, 2020)
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criteria provided, single submitter
Method: research
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Nemaline myopathy 8
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Department of Paediatrics and Adolescent Medicine, The University of Hong Kong
Accession: SCV001293796.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
We identified six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non-consanguineous southern Chinese. All unrelated patients carried … (more)
We identified six cases of nemaline myopathy 8 which involves the c.1516A>C variant, from five unrelated families of non-consanguineous southern Chinese. All unrelated patients carried a homozygous c.1516A>C p.(Thr506Pro) mutation, except for two siblings who carried compound heterozygous variants of another variant. Common prenatal features included reduced fetal movement, polyhydramnios, breech presentation, and clubfeet. Two pregnancies were terminated. Four live-born patients had postnatal features typical of nemaline myopathy 8. The length of survival ranged from 49 days to 17 months, with respiratory failure and infections being the principal causes of death. Haplotype analysis in three patients with homozygous mutation showed a shared haplotype block of 1.1727 cM spanning over the c.1516A>C variant, suggesting it is a southern Chinese-specific founder mutation. (less)
Observation 1:
Clinical Features:
Generalized hypotonia (present) , Bilateral ptosis (present) , Mask-like facies (present) , Multiple joint contractures (present) , Polyhydramnios (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
Observation 2:
Clinical Features:
Polyhydramnios (present) , Decreased fetal movement (present) , Generalized hypotonia (present) , Tented upper lip vermilion (present) , Muscular atrophy (present) , Flexion contracture (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
Observation 3:
Clinical Features:
No obvious fetal movement (observed from fetal ultrasound) (present)
Age: 60-69 weeks gestation
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
Comment on evidence:
The siblings of observation 2
Observation 4:
Clinical Features:
Generalized hypotonia (present) , Downslanted palpebral fissures (present) , Frontal bossing (present) , Bilateral ptosis (present) , Bilateral talipes equinovarus (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
Observation 5:
Clinical Features:
Bilateral talipes equinovarus (present) , Decreased fetal movement (present)
Age: 90-99 weeks gestation
Sex: female
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
Observation 6:
Clinical Features:
Polyhydramnios (present) , Generalized hypotonia (present) , Hypoventilation (present) , Arthrogryposis multiplex congenita (present) , Pathologic fracture (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Chinese
Geographic origin: Hong Kong
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Pathogenic
(Jan 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nemaline myopathy 8
Affected status: yes
Allele origin:
maternal
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Provincial Medical Genetics Program of British Columbia, University of British Columbia
Accession: SCV002496408.1
First in ClinVar: Apr 08, 2022 Last updated: Apr 08, 2022 |
Sex: male
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nemaline myopathy 8
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572633.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). In silico tool predictions suggest damaging effect … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.72; 3Cnet: 0.11). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000846771). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (3billion dataset / VCV000846771). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Anemia (present)
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Pathogenic
(Sep 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Nemaline myopathy 8
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016383.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Nemaline myopathy 8
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001214258.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, … (more)
For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KLHL40 protein function. ClinVar contains an entry for this variant (Variation ID: 846771). This missense change has been observed in individual(s) with nemaline myopathy and/or fetal akinesia deformation sequence (PMID: 23746549, 27762439, 31360996). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778022582, gnomAD 0.1%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 506 of the KLHL40 protein (p.Thr506Pro). (less)
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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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Founder Mutation c.1516A>C in KLHL40 Is a Frequent Cause of Nemaline Myopathy With Hyponatremia in Ethnic Chinese. | Lee HH | Journal of neuropathology and experimental neurology | 2019 | PMID: 31360996 |
Identification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence. | Chen TH | Prenatal diagnosis | 2016 | PMID: 27762439 |
Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. | Ravenscroft G | American journal of human genetics | 2013 | PMID: 23746549 |
Text-mined citations for rs778022582 ...
HelpRecord last updated Mar 17, 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.