ClinVar Miner

Submissions for variant NM_000166.6(GJB1):c.271G>A (p.Val91Met) (rs756928158)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000175537 SCV000227039 likely pathogenic not provided 2015-03-02 criteria provided, single submitter clinical testing
Invitae RCV000461635 SCV000544770 pathogenic Charcot-Marie-Tooth Neuropathy X 2020-02-07 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 91 of the GJB1 protein (p.Val91Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is present in population databases (rs756928158, ExAC 0.01%). This variant has been reported in several individuals affected with CMTX (PMID: 11140841, 11571214, 22464564, 27027447, 28097225, 27844031). ClinVar contains an entry for this variant (Variation ID: 195025). 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 C1). This missense change is located in a region of the GJB1 protein where a significant number of previously reported GJB1 missense mutations are found (PMID: 19448103, 22464564, 11325342, 7477983, 9592087). These observations suggest that missense substitutions within this region may affect protein function, but experiments have not been done to test this possibility for this specific missense change. For these reasons, this variant has been classified as Pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000175537 SCV001245763 pathogenic not provided 2018-03-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001249761 SCV001423794 pathogenic Charcot-Marie-Tooth Neuropathy X Type 1 2019-12-13 criteria provided, single submitter clinical testing The GJB1 c.271G>A (p.Val91Met) variant is a missense variant that has been reported in a heterozygous state in at least eight individuals with Charcot-Marie-Tooth neuropathy (Bissar-Tadmouri et al. 2000; Dobourg et al. 2001; Michelle et al. 2009; Arthur-Farraj et al. 2012; Tsai et al. 2016; Hong et al. 2017). Affected individuals presented with motor neuropathy, areflexia, ataxia, paresthesia of the feet, numbness and/or weakness of lower limbs, and sensorineural hearing loss in at least one affected individual. Age of onset was variable, but generally occurred in the first or second decade. The p.Val91Met variant was absent from 50 control individuals (Dobourg et al. 2001) and is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Functional studies in HeLa cells showed decreased expression of the p.Val91Met variant protein in the plasma membrane compared to controls (Tsai et al. 2016). In addition, the variant protein was mainly localized to the cytoplasm and showed fewer gap junction plaques at the intercellular boundaries compared to wild-type. Additional tests were conducted in HEK293T cells where Ca2+ signaling propagation was evaluated. Impaired gap junction permeability was observed and the onset-to-peak duration of the signal was longer in cells expressing the p.Val91Met variant compared to those expressing wild-type protein (Tsai et al. 2016). The p.Val91Met variant is located in the second transmembrane domain which is suggested to be important for protein conformation. Based on the collective evidence, the p.Val91Met variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1.

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