ClinVar Miner

Submissions for variant NM_004004.6(GJB2):c.2T>C (p.Met1Thr) (rs371086981)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171533 SCV001334318 likely pathogenic Nonsyndromic hearing loss and deafness 2020-02-19 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_Moderate; ClinVar Variation IDs: 17002, 17004). This variant has been observed in 0.002891% (1/34592) of Latino alleles in gnomAD v2.1.1 and was absent from gnomAD v3 (PM2). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored a known pathogenic variant (PM3_Supporting; Athena Diagnostics internal data, SCV001143666.1). A different pathogenic missense variant (p.Met1Val) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar ID: 44729). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PVS1_Moderate, PM2, PM3_Supporting, PM5).
Counsyl RCV000409687 SCV000487741 likely pathogenic Deafness, autosomal recessive 1A 2016-10-11 criteria provided, single submitter clinical testing
Counsyl RCV000410366 SCV000487742 likely pathogenic Deafness, autosomal dominant 3a 2016-10-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781415 SCV000919428 uncertain significance not specified 2017-10-03 criteria provided, single submitter clinical testing Variant summary: The GJB2 c.2T>C (p.Met1Thr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/243992 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GJB2 variant (0.0003376). In addition, one other clinical diagnostic laboratory classified this variant as likely pathogenic and one reputable database lists this variant as VUS, all without evidence for independent evaluation. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. 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. Because of the absence of clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS)-possibly pathogenic until additional information becomes available.
Athena Diagnostics Inc 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.
Invitae RCV000991847 SCV001225573 likely pathogenic not provided 2019-10-09 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, ExAC 0.01%). This variant has not been reported in the literature in individuals with GJB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 371781). A different variant (c.1A>G) giving rise to the same protein effect observed here (Initiator codon) has been determined to be pathogenic (PMID: 12189493, 9482292, 20146813, 18941476, 10218527). This suggests that this variant is also likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000991847 SCV001818526 pathogenic not provided 2021-03-02 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 a significant frequency in large population cohorts (Lek et al., 2016); 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)

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