Submissions for variant NM_004004.6(GJB2):c.505T>C (p.Cys169Arg)

dbSNP: rs760489970

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lifecell International Pvt. Ltd	RCV003232335	SCV003930314	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A		criteria provided, single submitter	clinical testing	A Heterozygous Missense variant c.505T>C in Exon 2 of the GJB2 gene that results in the amino acid substitution p.Cys169Arg was identified. The observed variant is novel in gnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. A different missense variation in the same codon has been reported in deafness patients (Mahfood M, et.al., 2021). ClinVar has also classified this variant as Pathogenic [Variation ID: 1064641]. For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558824	SCV004295449	likely pathogenic	not provided	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 169 of the GJB2 protein (p.Cys169Arg). This variant is present in population databases (rs760489970, gnomAD 0.006%). This missense change has been observed in individual(s) with deafness (PMID: 22695344, 28483220). ClinVar contains an entry for this variant (Variation ID: 1064641). 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 GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Cys169 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24551843, 25628337, 34354426). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV001374649	SCV001571572	likely pathogenic	nonsyndromic sensorineural hearing loss	2020-11-02	no assertion criteria provided	clinical testing