ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.280C>T (p.His94Tyr) (rs1602349087)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377073 SCV001574306 likely pathogenic Charcot-Marie-Tooth Neuropathy X 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 94 of the GJB1 protein (p.His94Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 28768847, Invitae). ClinVar contains an entry for this variant (Variation ID: 637580). Experimental studies have shown that this variant affects GJB1 protein function (PMID: 11325342). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.His94 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 11571214, 22464564), which suggests that this may be a clinically significant amino acid residue. 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.
Inherited Neuropathy Consortium RCV000789828 SCV000929212 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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