Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PS4(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18334946;26694549;28839118;30076350. The cataract phenotype/s reported for this variant are: Jellyfish-like, and Anterior cortical/nuclear. Additional phenotype/s reported in these individual/s are: latent nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320
ClinVar Genomic variation as it relates to human health
NM_005267.5(GJA8):c.134G>C (p.Trp45Ser)
Germline
Classification
Help
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.
(6)
Help
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.
Pathogenic/Likely pathogenic
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_005267.5(GJA8):c.134G>C (p.Trp45Ser)
Variation ID: 217335 Accession: VCV000217335.10
- 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 Jan 15, 2016 Oct 8, 2024 Sep 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005267.5:c.134G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005258.2:p.Trp45Ser missense NC_000001.11:g.147908089G>C NC_000001.10:g.147380216G>C NG_016242.1:g.10271G>C - Protein change
- W45S
- Other names
- -
- Canonical SPDI
- NC_000001.11:147908088:G: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.
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Trans-Omics for Precision Medicine (TOPMed) 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
- 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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| GJA8 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
241 | 528 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
no assertion criteria provided
|
Jul 29, 2016 | RCV000203313.1 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 6, 2023 | RCV000644439.9 | |
|
GJA8-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Jan 12, 2024 | RCV003897434.2 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 21, 2023)
|
criteria provided, single submitter
Method: curation
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Cataract 1 multiple types
Affected status: yes
Allele origin:
germline
|
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania
Accession: SCV005081851.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PS4(Supporting), … (more)
Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PS4(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18334946;26694549;28839118;30076350. The cataract phenotype/s reported for this variant are: Jellyfish-like, and Anterior cortical/nuclear. Additional phenotype/s reported in these individual/s are: latent nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 (less)
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Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Cataract 1 multiple types
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002573030.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJA8-related disorder (ClinVar ID: VCV000217335 / PMID: 18334946). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549). Different missense changes at the same codon (p.Trp45Arg, p.Trp45Leu) have been reported to be associated with GJA8-related disorder (ClinVar ID: VCV000845873 / PMID: 28392901 , 30498267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Congenital aphakia (present) , Microcornea (present) , Microphthalmia (present) , Developmental cataract (present)
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Pathogenic
(Sep 06, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000766134.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). Advanced … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). 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. ClinVar contains an entry for this variant (Variation ID: 217335). This missense change has been observed in individual(s) with bilateral congenital cataracts (PMID: 18334946, 26694549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the GJA8 protein (p.Trp45Ser). (less)
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Pathogenic
(Jan 12, 2024)
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no assertion criteria provided
Method: clinical testing
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GJA8-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004717611.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a … (more)
The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a kindred with congenital cataracts and microcornea (Vanita et al. 2008. PubMed ID: 18334946). This variant has been reported in additional, unrelated individuals with congenital cataracts (Javadiyan et al. 2017. PubMed ID: 28839118; Ma et al. 2016. PubMed ID: 26694549; Zamani et al. 2022. PubMed ID: 35754085). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic. (less)
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Pathogenic
(Jan 09, 2015)
|
no assertion criteria provided
Method: research
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Developmental cataract
Affected status: yes
Allele origin:
de novo
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Eye Genetics Research Group, Children's Medical Research Institute
Accession: SCV000256015.1
First in ClinVar: Jan 15, 2016 Last updated: Jan 15, 2016
Comment:
Family 20
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Pathogenic
(Jul 29, 2016)
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no assertion criteria provided
Method: clinical testing
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Developmental cataract
Affected status: yes
Allele origin:
inherited
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Department of Ophthalmology, Flinders University
Accession: SCV000297750.1
First in ClinVar: Jan 15, 2016 Last updated: Jan 15, 2016 |
|
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJA8-related disorder (ClinVar ID: VCV000217335 / PMID: 18334946). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549). Different missense changes at the same codon (p.Trp45Arg, p.Trp45Leu) have been reported to be associated with GJA8-related disorder (ClinVar ID: VCV000845873 / PMID: 28392901 , 30498267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). 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. ClinVar contains an entry for this variant (Variation ID: 217335). This missense change has been observed in individual(s) with bilateral congenital cataracts (PMID: 18334946, 26694549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the GJA8 protein (p.Trp45Ser).
Comment:
The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a kindred with congenital cataracts and microcornea (Vanita et al. 2008. PubMed ID: 18334946). This variant has been reported in additional, unrelated individuals with congenital cataracts (Javadiyan et al. 2017. PubMed ID: 28839118; Ma et al. 2016. PubMed ID: 26694549; Zamani et al. 2022. PubMed ID: 35754085). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic.
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. |
Comment:
Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Moderate), PM1(Supporting), PS4(Supporting), PM2(Supporting), PM5(Supporting), PP3. Original variant report: PMID:18334946;26694549;28839118;30076350. The cataract phenotype/s reported for this variant are: Jellyfish-like, and Anterior cortical/nuclear. Additional phenotype/s reported in these individual/s are: latent nystagmus. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GJA8-related disorder (ClinVar ID: VCV000217335 / PMID: 18334946). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26694549). Different missense changes at the same codon (p.Trp45Arg, p.Trp45Leu) have been reported to be associated with GJA8-related disorder (ClinVar ID: VCV000845873 / PMID: 28392901 , 30498267). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA8 function (PMID: 21228318, 25003127). 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. ClinVar contains an entry for this variant (Variation ID: 217335). This missense change has been observed in individual(s) with bilateral congenital cataracts (PMID: 18334946, 26694549). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the GJA8 protein (p.Trp45Ser).
Comment:
The GJA8 c.134G>C variant is predicted to result in the amino acid substitution p.Trp45Ser. This variant has been reported to segregate with disease in a kindred with congenital cataracts and microcornea (Vanita et al. 2008. PubMed ID: 18334946). This variant has been reported in additional, unrelated individuals with congenital cataracts (Javadiyan et al. 2017. PubMed ID: 28839118; Ma et al. 2016. PubMed ID: 26694549; Zamani et al. 2022. PubMed ID: 35754085). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Given the evidence, we interpret this variant as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Unique presentation of congenital cataract concurrent with microcornea, microphthalmia plus posterior capsule defect in monozygotic twins caused by a novel GJA8 mutation. | Zhang H | Eye (London, England) | 2019 | PMID: 30498267 |
| Targeted next-generation sequencing as a comprehensive test for Mendelian diseases: a cohort diagnostic study. | Sun Y | Scientific reports | 2018 | PMID: 30076350 |
| High-Throughput Genetic Screening of 51 Pediatric Cataract Genes Identifies Causative Mutations in Inherited Pediatric Cataract in South Eastern Australia. | Javadiyan S | G3 (Bethesda, Md.) | 2017 | PMID: 28839118 |
| 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 |
| A novel mutation in GJA8 associated with jellyfish-like cataract in a family of Indian origin. | Vanita V | Molecular vision | 2008 | PMID: 18334946 |
Text-mined citations for rs864309688 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 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.