Submissions for variant NM_004004.6(GJB2):c.456C>A (p.Tyr152Ter)

dbSNP: rs111033420

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037856	SCV000061518	likely pathogenic	Rare genetic deafness	2009-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000578957	SCV000680740	pathogenic	not provided	2023-04-17	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation, as the last 75 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12865758, 18580690, 19366456, 26444186, 19081147, 17666888)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488358	SCV001339228	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.456C>A (p.Tyr152X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251060 control chromosomes (gnomAD). c.456C>A has been reported in the literature, either as a single heterozygous occurrence or in compound heterozygosity with other variants, in multiple individuals affected with hearing loss (e.g. Dai_2009, Pandya_2003, Putcha_2007, Schimmenti_2008, Tayoun_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12865758, 19366456, 17666888, 18580690, 26444186). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; all submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000578957	SCV001405519	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr152*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 75 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033420, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with autosomal recessive deafness (PMID: 19366456). ClinVar contains an entry for this variant (Variation ID: 44753). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.
Counsyl	RCV000667555	SCV000792027	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2017-06-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000667555	SCV001463366	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-09-16	no assertion criteria provided	clinical testing