Submissions for variant NM_000083.3(CLCN1):c.763G>T (p.Gly255Trp)

gnomAD frequency: 0.00001  dbSNP: rs746691295

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518447	SCV000612796	likely pathogenic	not provided	2022-11-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with recessive myotonia congenita. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815779	SCV000956249	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 255 of the CLCN1 protein (p.Gly255Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 29606556; Invitae). ClinVar contains an entry for this variant (Variation ID: 447070). 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 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323583	SCV004029004	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.763G>T (p.Gly255Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251422 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.763G>T has been reported in the literature in a compound heterozygous individual affected with Myotonia congenita (Stunnenberg_2018). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29606556). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.