ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.208C>G (p.Pro70Ala) (rs878853697)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231475 SCV000283686 pathogenic Charcot-Marie-Tooth Neuropathy X 2017-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 70 of the GJB1 protein (p.Pro70Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Charcot-Marie-Tooth disease type 1X (CMT1X) in a single family (PMID: 10873293). This variant has also been reported in multiple unrelated individuals affected with CMT1X (PMID: 21692908, Invitae). ClinVar contains an entry for this variant (Variation ID: 237122). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000484101 SCV000565042 likely pathogenic not provided 2019-04-08 criteria provided, single submitter clinical testing Identified in 2 unrelated families with a mild Charcot-Marie-Tooth 1X phenotype (Ionasescu et al., 1998; Siskind et al., 2011).; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic; This variant is associated with the following publications: (PMID: 21291455, 21692908, 10873293)
Inherited Neuropathy Consortium RCV000789229 SCV000928581 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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