ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
Integrated Genetics/Laboratory Corporation of America 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.

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