ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.112G>A (p.Val38Met) (rs879254012)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235629 SCV000293164 pathogenic not provided 2015-09-19 criteria provided, single submitter clinical testing The V38M variant in the GJB1 gene has been reported previously in the Human Gene Mutation Database in association with Charcot-Marie-Tooth disease (Stenson et al., 2014). The V38M mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V38M mutation is a conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Valine are tolerated across species. A functional study showed that the V38M mutation alters conductance-voltage relation that would likely impact channel function, and an additional study showed that protein with the V38M variant was located in the Golgi apparatus rather than at the cell membrane (Oh et al., 1997; Yum et al., 2002).
Athena Diagnostics Inc RCV000235629 SCV000613476 pathogenic not provided 2016-11-29 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000235629 SCV000883941 pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing The p.Val38Met was first reported in a single family with X-linked dominant Charcot-Marie-Tooth neuropathy (CMT), where the variant was demonstrated to segregate with disease (Orth 1994). This variant is in the first transmembrane domain of the GJB1 channel, and functional studies of the variant protein showed altered conductance-voltage compared to WT suggestive of channel closure (Oh 1998). Variants that change codon 38 to a different amino acid and others nearby have been reported in association with CMT (Hong 2017, Karadima 2004). The p.Val38Met is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) and has been reported to the ClinVar database with a pathogenic classification (Variation ID: 245946). Altogether the p.Val38Met variant is considered to be pathogenic.
Invitae RCV000793260 SCV000932606 pathogenic Charcot-Marie-Tooth Neuropathy X 2018-08-20 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 38 of the GJB1 protein (p.Val38Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with X-linked dominant Charcot-Marie-Tooth disease in a family (PMID: 7833935). ClinVar contains an entry for this variant (Variation ID: 245946). Experimental studies have shown that this missense change alters conductance-voltage relation that would likely impact channel function, and that protein is retained in Golgi apparatus rather than at the cell membrane  (PMID: 9354338, 12460545). Variants that disrupt the p.Val38 amino acid residue in GJB1 have been observed in affected individuals (PMID: 14991359, 28448691). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Inherited Neuropathy Consortium RCV000789918 SCV000929303 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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