Submissions for variant NM_021954.4(GJA3):c.7G>T (p.Asp3Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003518792	SCV004295448	pathogenic	Cataract 14 multiple types	2023-04-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJA3 function (PMID: 22843197, 23302783). 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 GJA3 protein function. This missense change has been observed in individuals with congenital cataract (PMID: 16885921, 29934635). 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 aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 3 of the GJA3 protein (p.Asp3Tyr).
Dept. Genetics and Cancer, Menzies Institute for Medical Research, University of Tasmania	RCV003518792	SCV005081809	likely pathogenic	Cataract 14 multiple types	2023-01-21	criteria provided, single submitter	curation	Variant identified and curated during a GJA3 specific review of the literature in relation to pediatric or congenital cataract. ACMG-AMP criteria applied: PP1(Strong), PM1, PS4(supporting), PM2(supporting), PP3. Original variant report: PMID:16885921;29934635. The cataract phenotype/s reported for this variant is: Zonular pulverulent and Lamellar. Gene review and curation guidelines are outlined in: https://doi.org/10.1080/17469899.2023.2160320