Submissions for variant NM_004004.6(GJB2):c.2T>C (p.Met1Thr)

gnomAD frequency: 0.00003  dbSNP: rs371086981

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hearing Loss Variant Curation Expert Panel	RCV001171533	SCV001334318	pathogenic	Nonsyndromic genetic hearing loss	2024-03-28	reviewed by expert panel	curation	The c.2T>C (p.Met1Thr) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 550716, 551915). This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored an assumed trans pathogenic variant (0.5 PM3_Supporting points; Athena Diagnostics internal data, SCV001143666.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023).
Counsyl	RCV000409687	SCV000487741	likely pathogenic	Autosomal recessive nonsyndromic hearing loss 1A	2016-10-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000410366	SCV000487742	likely pathogenic	Autosomal dominant nonsyndromic hearing loss 3A	2016-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171533	SCV000919428	likely pathogenic	Nonsyndromic genetic hearing loss	2022-08-22	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249204 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Non-Syndromic Hearing Loss and no experimental evidence demonstrating its impact on protein function have been reported. This variant disrupts the start codon for protein translation (ATG becomes ACG) and the next start codon is 32 amino acids downstream. Variants affecting the same codon (M1V) and other codons within the N terminal 32 amino acids (such as L6P, Q7P, L10P, G12V, R32C, etc) have been reported in many affected individuals, suggesting the functional importance of this codon and the N terminal region of this protein (example: PMID: 29605365, PMID: 9482292). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic(n=3)/likely pathogenic(n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Athena Diagnostics	RCV000991847	SCV001143666	pathogenic	not provided	2018-11-09	criteria provided, single submitter	clinical testing	The variant disrupts the natural start codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991847	SCV001225573	pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the GJB2 mRNA. The next in-frame methionine is located at codon 34. This variant is present in population databases (rs371086981, gnomAD 0.003%). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive nonsyndromic deafness (PMID: 9482292, 29605365). ClinVar contains an entry for this variant (Variation ID: 371781). Studies have shown that disruption of the initiator codon alters GJB2 gene expression (PMID: 12189493). This variant disrupts a region of the GJB2 protein in which other variant(s) (p.Gly12Val) have been determined to be pathogenic (PMID: 10982180, 19371219, 24158611, 25288386). 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	RCV000991847	SCV001818526	pathogenic	not provided	2022-01-07	criteria provided, single submitter	clinical testing	Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in one individual with a low grade glioma from a cohort of cancer patients as part of a large investigation of cancer predisposition variants (Huang et al., 2018); This variant is associated with the following publications: (PMID: 29625052)
PreventionGenetics, part of Exact Sciences	RCV004530500	SCV004116825	likely pathogenic	GJB2-related disorder	2022-11-22	criteria provided, single submitter	clinical testing	The GJB2 c.2T>C variant is predicted to disrupt the translation initiation site (Start loss). To our knowledge, this variant has not been reported in a patient with hearing loss or deafness. However, two other variants that also result in start loss (p.Met1Ile, p.Met1Val) have been reported in patients with nonsyndromic hearing loss (Huang et al. 2018. PubMed ID: 29605365; Estivill et al. 1998. PubMed ID: 9482292). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-20763719-A-G). This variant is interpreted as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005010302	SCV005632126	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	2024-05-04	criteria provided, single submitter	clinical testing