Submissions for variant NM_004004.6(GJB2):c.19C>T (p.Gln7Ter)

gnomAD frequency: 0.00001  dbSNP: rs111033451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211718	SCV000061482	likely pathogenic	Rare genetic deafness	2009-09-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000037820	SCV000221053	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2015-01-21	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037820	SCV000698233	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-02-11	criteria provided, single submitter	clinical testing	Variant summary: The c.19C>T variant results in a premature termination codon, predicted to cause a truncated or absent GJB2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.269dupT/p.Val91fsX11, c.334_335delAA/p.Lys112fsX2). One in-silico tool predicts damaging outcome for this variant. This variant has been reported predominantly in Ecuadorian population in patients with syndromic or non-syndromic hearing loss. This variant is not found in 121382 control chromosomes. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic.
Ambry Genetics	RCV000624822	SCV000742949	pathogenic	Inborn genetic diseases	2017-10-02	criteria provided, single submitter	clinical testing
Invitae	RCV001389832	SCV001591339	pathogenic	not provided	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln7*) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 220 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs111033451, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with GJB2-related conditions (PMID: 12865758, 25085072, 31370293). ClinVar contains an entry for this variant (Variation ID: 44728). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Cys202*) have been determined to be pathogenic (PMID: 23141775). 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.
GeneDx	RCV001389832	SCV001872958	likely pathogenic	not provided	2021-07-19	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 220 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27535533, 25085072, 12865758, 31370293)