Submissions for variant NM_004004.6(GJB2):c.31_68del (p.Gly11fs)

gnomAD frequency: 0.00001  dbSNP: rs397516873

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037837	SCV000061499	pathogenic	Rare genetic deafness	2012-04-17	criteria provided, single submitter	clinical testing	The Gly11fs variant in GJB2 has been reported in one individual with hearing los s (Denoyelle 1997). This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 11 and lead to a premature termination codon 24 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
Counsyl	RCV000411009	SCV000487542	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-03-14	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000517627	SCV000613511	pathogenic	not provided	2017-03-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000517627	SCV001167921	pathogenic	not provided	2018-06-18	criteria provided, single submitter	clinical testing	The c.31_68del38 variant in the GJB2 gene has been reported previously in association with hearing loss (Snoeckx et al., 2005; Dodson et al., 2011; Beck et al., 2014). The deletion causes a frameshift starting with codon Glycine 11, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Gly11LeufsX24. This variant is predicted to cause loss of normal protein function through protein truncation. The variant is observed in 5/110262 (0.0045%) alleles from individuals of European background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001527052	SCV001737887	pathogenic	Nonsyndromic genetic hearing loss	2021-06-09	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.31_68del38 (p.Gly11LeufsX24) 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 allele was found at a frequency of 2e-05 in 250064 control chromosomes. c.31_68del38 has been reported in the literature in multiple individuals affected with Non-Syndromic Hearing Loss (e.g. Denoyelle_1997, Janecke_2002, Dodson_2011, Beck_2015). 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. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000517627	SCV001961392	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV000517627	SCV002110910	pathogenic	not provided	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly11Leufs*24) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 216 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs397516873, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with autosomal recessive non-syndromic deafness (PMID: 9336442, 12189487, 16380907, 21465647, 25214170). This variant is also known as 31del38. ClinVar contains an entry for this variant (Variation ID: 44738). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Leu213*) 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.
PreventionGenetics, part of Exact Sciences	RCV003904923	SCV004724624	pathogenic	GJB2-related condition	2024-01-05	criteria provided, single submitter	clinical testing	The GJB2 c.31_68del38 variant is predicted to result in a frameshift and premature protein termination (p.Gly11Leufs*24). This variant was reported in several individuals with autosomal recessive deafness (Denoyelle et al. 1997. PubMed ID: 9336442; Dodson et al. 2011. PubMed ID: 21465647; Tang et al. 2006. PubMed ID: 17041943; and several other reports). This variant is reported in 0.0045% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic and this variant has been consistently classified as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/44738/). This variant is interpreted as pathogenic.
Counsyl	RCV000409896	SCV000487541	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-03-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000409896	SCV002086067	pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2020-07-24	no assertion criteria provided	clinical testing