ClinVar Genomic variation as it relates to human health
NM_005267.5(GJA8):c.134G>T (p.Trp45Leu)
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_005267.5(GJA8):c.134G>T (p.Trp45Leu)
Variation ID: 845873 Accession: VCV000845873.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.2 1: 147908089 (GRCh38) [ NCBI UCSC ] 1: 147380216 (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 14, 2024 Sep 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005267.5:c.134G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005258.2:p.Trp45Leu missense NC_000001.11:g.147908089G>T NC_000001.10:g.147380216G>T NG_016242.1:g.10271G>T - Protein change
- W45L
- Other names
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- Canonical SPDI
- NC_000001.11:147908088:G: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.
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- Links
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
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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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GJA8 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
186 | 470 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 27, 2023 | RCV001049034.7 |
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
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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
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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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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cataract 1 multiple types
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557721.1
First in ClinVar: Aug 08, 2022 Last updated: Aug 08, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a likely mechanism of disease in this gene and is associated with cataract 1, multiple types (MIM#116200). While loss of function has been described for missense variants in this gene (OMIM), dominant negative is a likely mechansim because this protein forms multimers (PMID: 33218330) and variants resulting in protein truncation are prevalent in the general population (gnomAD). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to leucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Pathogenic missense variants are clustered within the connexin domain (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic and likely pathogenic, and observed in two unrelated families with cataracts. Additionally, it has been observed de novo in another individual with cataracts (ClinVar, PMID: 33494148, PMID: 29464339, PMID: 28392901). (SP) 0902 - This variant has moderate evidence for segregation with disease. This variant has segregated within a large family with cataracts, microphthalmia and nystagmus (PMID: 29464339). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Pathogenic
(Sep 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cataract 1 multiple types
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001213067.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 28392901, 29464339). It has also been observed to segregate with disease … (more)
This missense change has been observed in individuals with autosomal dominant congenital cataracts (PMID: 28392901, 29464339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 845873). 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) performed at Invitae indicates that this missense variant is expected to disrupt GJA8 protein function. This variant disrupts the p.Trp45 amino acid residue in GJA8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18334946, 21228318, 25003127, 26694549). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with leucine, which is neutral and non-polar, at codon 45 of the GJA8 protein (p.Trp45Leu). (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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Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0-25 with Bilateral Cataracts. | Bell S | Genes | 2021 | PMID: 33494148 |
Identification and functional analysis of a novel missense mutation in GJA8, p.Ala69Thr. | Li D | BMC ophthalmology | 2020 | PMID: 33218330 |
New GJA8 variants and phenotypes highlight its critical role in a broad spectrum of eye anomalies. | Ceroni F | Human genetics | 2019 | PMID: 29464339 |
Mutation analysis of connexin 50 gene among Iranian families with autosomal dominant cataracts. | Mohebi M | Iranian journal of basic medical sciences | 2017 | PMID: 28392901 |
Sporadic and Familial Congenital Cataracts: Mutational Spectrum and New Diagnoses Using Next-Generation Sequencing. | Ma AS | Human mutation | 2016 | PMID: 26694549 |
Structure-function correlation analysis of connexin50 missense mutations causing congenital cataract: electrostatic potential alteration could determine intracellular trafficking fate of mutants. | Sarkar D | BioMed research international | 2014 | PMID: 25003127 |
Different consequences of cataract-associated mutations at adjacent positions in the first extracellular boundary of connexin50. | Tong JJ | American journal of physiology. Cell physiology | 2011 | PMID: 21228318 |
Text-mined citations for rs864309688 ...
HelpRecord last updated Feb 20, 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.