ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.524dup (p.Asn175fs) (rs1569215346)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688157 SCV000815759 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-02-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the GJB1 gene (p.Asn175Lysfs*68). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 109 amino acids of the GJB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with X-linked Charcot-Marie-Tooth disease or CMTX (PMID: 8266101). ClinVar contains an entry for this variant (Variation ID: 567945). Experimental studies have shown that this nonsense change fails to form functional channels with wild-type connexin and results in no detectable GJB1 protein, both in vitro as well as in animal models of disease (PMID: 7946361, 9364054, 10207904). A different truncation (p.Arg220*) that lies downstream of this variant has been determined to be pathogenic (PMID: 7477983, 8162049, 9364054, 21291455, 9364054, 9592087). This suggests that deletion of this region of the GJB1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000711358 SCV000841719 pathogenic not provided 2018-03-08 criteria provided, single submitter clinical testing
Inherited Neuropathy Consortium RCV000789813 SCV000929197 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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