ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.658C>T (p.Arg220Ter) (rs104894814)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000236998 SCV000227040 pathogenic not provided 2015-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000236998 SCV000292877 pathogenic not provided 2018-03-05 criteria provided, single submitter clinical testing The R220X nonsense variant in the GJB1 gene has been reported previously in association with CMTX1 (Fairweather et al., 1994) and is associated with mild to moderate symptoms in both males and females (Deschênes et al., 1997). R220X has also been reported in association with CMT2 (Høyer et al., 2014). This pathogenic variant is predicted to cause loss of normal protein function through protein truncation as the last 64 amino acid residues are lost. The R220X variant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of R220X is consistent with the diagnosis of CMTX1 in this individual.
Invitae RCV000466155 SCV000544782 pathogenic Charcot-Marie-Tooth Neuropathy X 2019-10-28 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the GJB1 mRNA at codon 220 (p.Arg220*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 64 amino acids (~23%) of the GJB1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple families affected with X-linked dominant Charcot-Marie-Tooth disease and has been observed to co-segregate with disease (PMID: 7477983, 8162049, 9364054, 21291455). ClinVar contains an entry for this variant (Variation ID: 10435). This variant has been reported to alter the localization and voltage gating properties of the GJB1 protein (also called Cx32) (PMID: 9364054, 9592087). Studies done in another experimental system failed to detect an effect of this variant on GJB1 protein function, however, these results did not preclude a deleterious role for this variant (PMID: 8816997). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000236998 SCV000613499 pathogenic not provided 2016-01-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000011180 SCV000894502 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2018-10-31 criteria provided, single submitter clinical testing
OMIM RCV000011180 SCV000031407 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2012-02-01 no assertion criteria provided literature only

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