VCV002915341.2 - ClinVar

NM_005267.5(GJA8):c.133T>C (p.Trp45Arg)

Germline

Classification

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.

(2)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005267.5(GJA8):c.133T>C (p.Trp45Arg)

Variation ID: 2915341 Accession: VCV002915341.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q21.2 1: 147908088 (GRCh38) [ NCBI UCSC ] 1: 147380215 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Feb 20, 2024	Jul 23, 2024	Nov 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_005267.5:c.133T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005258.2:p.Trp45Arg	missense
NC_000001.11:g.147908088T>C
NC_000001.10:g.147380215T>C
NG_016242.1:g.10270T>C
NG_016242.2:g.10295T>C

... more HGVS ... less HGVS

Protein change

W45R

Other names

Canonical SPDI

NC_000001.11:147908087:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	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.
Cataract 1 multiple types	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Nov 15, 2023	RCV003620421.3

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.
Pathogenic (Nov 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Cataract 1 multiple types Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004551482.1 First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024	Publications: PubMed (5) PubMed: 30498267‚ 18334946‚ 21228318‚ 25003127‚ 26694549 Comment: This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 45 of the GJA8 protein … (more) This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 45 of the GJA8 protein (p.Trp45Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 30498267). It has also been observed to segregate with disease in related individuals. 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 with a positive predictive value of 95%. 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. (less)
Uncertain significance (Jan 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Cataract 1 multiple types Affected status: yes Allele origin: germline	Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania Accession: SCV005081849.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 30498267 Comment: Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PM1(Supporting), PM2(Supporting), PM5(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: PM1(Supporting), PM2(Supporting), PM5(Supporting), PP1, PP3. Original variant report: PMID:30498267. The cataract phenotype reported for this variant is: Nuclear. Additional phenotype/s reported in these individual/s are: Microcornea, microphthalmia and posterior capsule defect. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320 (less)

Comment:

This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 45 of the GJA8 protein (p.Trp45Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital cataract (PMID: 30498267). It has also been observed to segregate with disease in related individuals. 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 with a positive predictive value of 95%. 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.

Comment:

Variant identified and curated during a GJA8 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PM1(Supporting), PM2(Supporting), PM5(Supporting), PP1, PP3. Original variant report: PMID:30498267. The cataract phenotype reported for this variant is: Nuclear. Additional phenotype/s reported in these individual/s are: Microcornea, microphthalmia and posterior capsule defect. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320

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:

Citations for germline classification of this variant

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
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 this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_005267.5(GJA8):c.133T>C (p.Trp45Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...