ClinVar Genomic variation as it relates to human health
NM_015681.6(B9D1):c.341G>A (p.Arg114Gln)
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_015681.6(B9D1):c.341G>A (p.Arg114Gln)
Variation ID: 1064604 Accession: VCV001064604.9
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p11.2 17: 19347784 (GRCh38) [ NCBI UCSC ] 17: 19251097 (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 8, 2021 Feb 28, 2024 Jun 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_015681.6:c.341G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056496.1:p.Arg114Gln missense NM_001321214.2:c.341G>A NP_001308143.1:p.Arg114Gln missense NM_001321215.3:c.341G>A NP_001308144.1:p.Arg114Gln missense NM_001321216.2:c.341G>A NP_001308145.1:p.Arg114Gln missense NM_001321217.2:c.341G>A NP_001308146.1:p.Arg114Gln missense NM_001321218.2:c.341G>A NP_001308147.1:p.Arg114Gln missense NM_001321219.2:c.341G>A NP_001308148.1:p.Arg114Gln missense NM_001330149.2:c.341G>A NP_001317078.1:p.Arg114Gln missense NM_001368769.2:c.-20G>A 5 prime UTR NM_015681.4:c.341G>A NC_000017.11:g.19347784C>T NC_000017.10:g.19251097C>T NG_031885.2:g.35410G>A LRG_686:g.35410G>A LRG_686t1:c.341G>A LRG_686p1:p.Arg114Gln - Protein change
- R114Q
- Other names
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- Canonical SPDI
- NC_000017.11:19347783:C:T
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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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B9D1 | - | - |
GRCh38 GRCh37 |
198 | 335 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Feb 15, 2022 | RCV001726509.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Mar 29, 2023 | RCV001871960.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Apr 17, 2023 | RCV003230666.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 2, 2023 | RCV003234061.1 |
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
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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
(-)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome 27
Phenotypic concordance: Yes
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
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Kids Neuroscience Centre, Sydney Children's Hospitals Network
Accession: SCV001571523.2
First in ClinVar: Oct 08, 2021 Last updated: Dec 18, 2021 |
Comment:
We are unable to detect any normally spliced B9D1 transcripts produced from the c.341G>A variant allele. Skipping of exon 4 (r.245_341del) induced by the NM_015681.3:c.341G>A … (more)
We are unable to detect any normally spliced B9D1 transcripts produced from the c.341G>A variant allele. Skipping of exon 4 (r.245_341del) induced by the NM_015681.3:c.341G>A variant causes a frameshift, encoding 44 missense amino acids and a premature termination codon (p.(Trp82Cysfs*45)). These transcripts are not predicted to be targeted by nonsense mediated decay (NMD) as the premature termination codon is encoded within the terminal exon for all B9D1 isoforms. These mis-spliced transcripts are likely to produce truncated B9D1 proteins. ENST00000261499.4; NM_015681.3 p.(Trp82Cysfs*45) / ENST00000461069.2 p.(Trp82Cysfs*111) / ENST00000575403.1; NM_001243475.2 p.(Trp82Cysfs*59) ENST00000477478.2 p.(Trp82Cysfs*70) Mis-spliced B9D1 transcripts with exon 4 skipping encode B9D1 protein lacking 123 amino acids, including 93 amino acids (p.(Trp82_Val174del) from the conserved B9 domain. A three nucleotide deletion resulting in loss of p.(Val174del) is previously reported as a pathogenic variant in ClinVar. Missense substitutions of p.(Gly165Cys), p.(Arg156Gln) and p.(Arg156Trp) within the B9 domain are also described as pathogenic variants in ClinVar. Therefore, it is the opinion of this laboratory that loss of 93 amino acids (p.(Trp82_Val174del)) from the conserved B9 domain is consistent with likely non/dysfunction of the encoded B9D1 protein. (less)
Sex: female
Tissue: Whole blood
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Likely pathogenic
(Feb 15, 2022)
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criteria provided, single submitter
Method: research
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Joubert syndrome 27
Affected status: unknown
Allele origin:
unknown
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: CSER_NCGENES_2
Accession: SCV002587040.1 First in ClinVar: Oct 29, 2022 Last updated: Oct 29, 2022
Comment:
B9D1 c.341G>A p.(Arg114Gln) is a rare missense variant which is predicted to change a single amino acid in the encoded protein from arginine to glutamine. … (more)
B9D1 c.341G>A p.(Arg114Gln) is a rare missense variant which is predicted to change a single amino acid in the encoded protein from arginine to glutamine. This variant is observed in gnomAD with a global minor allele frequency of 0.003% (7 alleles/250,806 alleles, 0 homozygotes). In addition, this variant alters the last nucleotide of exon 4 adjacent to the 5' splice donor site of B9D1 intron 4. This variant has been previously reported in one individual with Joubert syndrome (PMID 32622957, 34906502). Analysis of RNA from the affected individual suggested this variant results in exon 4 skipping (r.245_341del) and the introduction of a frameshift and premature termination codon. The resulting protein is expected to be truncated, lacking 123 amino acids and disrupting the conserved B9 domain (PMID 32622957, 34906502). Therefore, this variant is classified as likely pathogenic. (less)
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Number of individuals with the variant: 1
Clinical Features:
Macrocephaly (present) , Hypertelorism (present) , Autism (present) , Delayed speech and language development (present) , Frontal bossing (present) , Delayed gross motor development (present) … (more)
Macrocephaly (present) , Hypertelorism (present) , Autism (present) , Delayed speech and language development (present) , Frontal bossing (present) , Delayed gross motor development (present) , Intellectual disability, moderate (present) , Expressive language delay (present) , Macrocephaly at birth (present) , Depressed nasal bridge (present) , Severe expressive language delay (present) , Attention deficit hyperactivity disorder (present) , Macrocephaly at birth (present) (less)
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Likely pathogenic
(Apr 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Joubert syndrome and related disorders
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003928427.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Variant summary: B9D1 c.341G>A (p.Arg114Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: B9D1 c.341G>A (p.Arg114Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 5' splicing donor site and two predict the variant weakens the 5' donor site. Publications report experimental evidence that this variant indeed affects mRNA splicing, resulting in the skipping of exon 4, which produces a frameshift and premature termination codon (e.g. Katiyar_2020, Bournazos_2022). The variant allele was found at a frequency of 2.8e-05 in 250806 control chromosomes (gnomAD). c.341G>A has been reported in the literature in the compound hetrozygous state in an individual affected with Joubert Syndrome (Katiyar_2020). Together these data suggest the variant is likely associated with disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jun 02, 2023)
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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: SCV003930971.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
Previously reported in a patient with Joubert syndrome who also harbored a second variant in the B9D1 gene; however, phase is unknown as additional segregation … (more)
Previously reported in a patient with Joubert syndrome who also harbored a second variant in the B9D1 gene; however, phase is unknown as additional segregation data was not provided (Katiyar et al., 2020); Published functional studies demonstrate a damaging effect as this variant causes aberrant splicing and results in a null allele (Katiyar et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32622957, 34906502) (less)
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Likely pathogenic
(Mar 29, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial aplasia of the vermis
Meckel-Gruber syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002273311.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬† is likely to be tolerated. … (more)
An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4 and introduces a premature termination codon (PMID: 32622957). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 1064604). This variant has been observed in individual(s) with Joubert syndrome (PMID: 32622957). This variant is present in population databases (rs778260923, gnomAD 0.007%). This sequence change affects codon 114 of the B9D1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the B9D1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. (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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Standardized practices for RNA diagnostics using clinically accessible specimens reclassifies 75% of putative splicing variants. | Bournazos AM | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906502 |
Two novel B9D1 variants causing Joubert syndrome: Utility of mRNA and splicing studies. | Katiyar D | European journal of medical genetics | 2020 | PMID: 32622957 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs778260923 ...
HelpRecord last updated May 08, 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.