Submissions for variant NM_004004.6(GJB2):c.576del (p.Val193fs)

dbSNP: rs747847191

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000798022	SCV000937614	pathogenic	not provided	2021-05-17	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the GJB2 gene (p.Val193Cysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 34 amino acids of the GJB2 protein. This variant is present in population databases (rs747847191, ExAC 0.002%). This variant has been observed in several individuals affected with non-syndromic hearing loss (PMID: 12497637, 20553101, 17666888). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the p.Asn206 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been observed in individuals with GJB2-related conditions (PMID: 12172394, 14985372, 15070423, 15967879), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000798022	SCV001476381	pathogenic	not provided	2020-02-21	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV002487675	SCV002781359	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A; Mutilating keratoderma; Ichthyosis, hystrix-like, with hearing loss; Autosomal dominant keratitis-ichthyosis-hearing loss syndrome; Palmoplantar keratoderma-deafness syndrome; Knuckle pads, deafness AND leukonychia syndrome; Autosomal dominant nonsyndromic hearing loss 3A; X-linked mixed hearing loss with perilymphatic gusher	2022-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230592	SCV003929344	pathogenic	Nonsyndromic genetic hearing loss	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.576delA (p.Val193CysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. At-least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251358 control chromosomes (gnomAD). c.576delA has been reported in the literature as heterozygous and bi-allelic genotypes in individuals affected with Non-Syndromic Hearing Loss and hearing-impairment (examples: Zoll_2002, Putcha_2007 and Siem_2010). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV000798022	SCV004021402	likely pathogenic	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a patient with severe hearing impairment in published literature (Zoll et al., 2003); Frameshift variant predicted to result in protein truncation, as the last 34 amino acids are replaced with 2 different amino acids, 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: 29625052, 12497637)
Mayo Clinic Laboratories, Mayo Clinic	RCV000798022	SCV004225743	pathogenic	not provided	2022-05-18	criteria provided, single submitter	clinical testing	PM2, PM3, PVS1