ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.763G>A (p.Gly255Arg)

dbSNP: rs746691295
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000784894 SCV000923431 uncertain significance Congenital myotonia, autosomal dominant form 2019-01-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000784895 SCV000923432 uncertain significance Congenital myotonia, autosomal recessive form 2019-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002535707 SCV003492286 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 255 of the CLCN1 protein (p.Gly255Arg). This variant is present in population databases (rs746691295, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (Invitae). ClinVar contains an entry for this variant (Variation ID: 634429). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN1 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gly255 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 29606556; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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