Submissions for variant NM_004004.6(GJB2):c.195C>G (p.Tyr65Ter)

dbSNP: rs763572195

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778388	SCV000914616	likely pathogenic	GJB2-Related Disorders	2018-08-16	criteria provided, single submitter	clinical testing	The GJB2 c.195C>G (p.Tyr65Ter) variant is a stop-gained variant predicted to result in premature termination of the mature protein. The p.Tyr65Ter variant has been reported in at least three studies in which it is found in at least four individuals affected with congenital hearing loss including in two in a compound heterozygous state, in one in a heterozygous state and in a third allele of unknown zygosity (Estivill et al. 1998; Gasmelseed et al. 2004; Snoeckx et al. 2005). The first individual, in whom a diagnosis of Ushers syndrome was excluded and is described as a sporadic case affected with non-syndromic deafness according to accepted clinical criteria, carried the p.Tyr65Ter variant in a compound heterozygous state with a known pathogenic variant (c.35delG) (Estivill et al 1998). In the second study, the p.Tyr65Ter variant was found in two alleles, one of which was in a compound heterozygous state with a missense variant in an individual with congenital hearing impairment. No further details are given for the second allele (Snoeckx et al. 2005). The p.Tyr65Ter variant was also found in a heterozygous state in a third individual with postnatal onset moderate to profound hearing loss (Gasmelseed et al. 2004). In this case, however, the p.Tyr65Ter variant resulted from an alternative nucleotide change ie. c.195C>A. Control data are unavailable for the p.Tyr65Ter variant, which is not found in either the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium or Genome Aggregation Database in a region of good sequence coverage, so is presumed rare. Based on the evidence and the potential impact of stop-gained variants, the p.Tyr65Ter variant is classified as likely pathogenic for GJB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae	RCV001231552	SCV001404079	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr65*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 162 amino acid(s) of the GJB2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with deafness (PMID: 9482292, 16380907). ClinVar contains an entry for this variant (Variation ID: 631698). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys211Leufs*5) have been determined to be pathogenic (PMID: 9529365, 12910486, 20863150). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc.	RCV001835954	SCV002086061	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2021-02-16	no assertion criteria provided	clinical testing