Submissions for variant NM_004004.6(GJB2):c.592_600delinsCAGTGTTCATGACATTC (p.Val198_Gly200delinsGlnCysSerTer)

dbSNP: rs111033335

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211782	SCV000061528	pathogenic	Rare genetic deafness	2015-04-27	criteria provided, single submitter	clinical testing	The p.Val198fs variant in GJB2 has been reported in 3 individuals with hearing l oss (Tang 2006, Chan 2010, LMM unpublished data), 2 of whom were compound hetero zygous with a second pathogenic or likely pathogenic GJB2 variant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequen ce beginning at position 198 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. In summary, this variant meets our criteria to be classified as pa thogenic for hearing loss in an autosomal recessive manner (http://www.partners. org/personalizedmedicine/LMM) based on the predicted impact of the variant and m ultiple occurrences with pathogenic GJB2 variants in individuals with hearing lo ss.
Genetic Services Laboratory, University of Chicago	RCV000037866	SCV000247477	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2013-02-08	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727541	SCV000709616	pathogenic	not provided	2017-06-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271384	SCV000919426	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.592_600delins17 (p.Val198GlnfsX4) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 246636 control chromosomes (gnomAD and publication data). c.592_600delins17 has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (example: Tang _2006, and Chan_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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000727541	SCV002024247	pathogenic	not provided	2019-05-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000727541	SCV002028241	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	Identified in an additional patient with hearing loss in published literature, however, it was unclear if a second variant was identified (Tang et al., 2006); Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 29 amino acids are lost and replaced with 3 incorrect amino acids (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20154630, 17041943)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678892	SCV000805085	pathogenic	Hearing loss	2010-03-31	no assertion criteria provided	clinical testing