ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.540C>G (p.Phe180Leu) (rs771022595)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000701205 SCV000829995 uncertain significance Charcot-Marie-Tooth Neuropathy X 2018-06-11 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 180 of the GJB1 protein (p.Phe180Leu). 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 observed in an individual affected with Charcot-Marie-Tooth disease (CMT) (PMID: 16922730). Additionally, a different nucleotide change (c.538T>C), that results in the same amino acid substitution (p.Phe180Leu) has been reported in a family affected with CMT (PMID: 28448691). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). The observation of one or more missense substitutions at this codon (p.Phe180Leu and p.Phe180Ser) in affected individuals suggests that this may be a clinically significant residue (PMID: 16922730, 28448691, 10873293). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc RCV000991855 SCV001143681 likely pathogenic not provided 2019-05-22 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/195627 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in a likely critical domain of the protein.
Inherited Neuropathy Consortium RCV000789922 SCV000929307 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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