ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.568G>A (p.Gly190Arg) (rs369773321)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000711236 SCV000343271 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing
Invitae RCV000530513 SCV000636298 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-04-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 190 of the CLCN1 protein (p.Gly190Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs369773321, ExAC 0.001%). This variant has been reported in combination with other CLCN1 variants in several individuals affected with autosomal recessive myotonia congenita (Becker disease) (PMID: 23810313, 24349310, 24037712). ClinVar contains an entry for this variant (Variation ID: 289004). 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"). A different missense substitution at this codon (p.Gly190Ser) has been determined to be pathogenic (PMID: 23933576, 19697366, 22921319). This suggests that the glycine residue is critical for CLCN1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000711236 SCV000841568 likely pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Occurs in three or more cases with a recessive pathogenic variant in the same gene.

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