ClinVar Miner

Submissions for variant NM_000166.5(GJB1):c.151T>C (p.Phe51Leu) (rs876661269)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220727 SCV000279940 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing A F51L variant that is likely pathogenic has been identified in the GJB1 gene. The F51L variant has been reported previously in an individual with CMT and was not detected in 200 control individuals; however, information about parental testing was not provided and functional characterization of the variant was not performed (Wang et al., 2015). The F51L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F51L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with CMT neuropathy (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae RCV000471605 SCV000544777 pathogenic Charcot-Marie-Tooth Neuropathy X 2017-09-07 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 51 of the GJB1 protein (p.Phe51Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals affected with Charcot-Marie-Tooth disease (PMID: 26454100, 28071741, Invitae database). ClinVar contains an entry for this variant (Variation ID: 234871). Experimental studies have shown that this missense variant prevents the formation of gap junctions (PMID: 28071741). For these reasons, this variant has been classified as Pathogenic.

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