Submissions for variant NM_000083.3(CLCN1):c.1832G>A (p.Arg611His)

gnomAD frequency: 0.00001  dbSNP: rs763850295

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001163171	SCV001325182	likely benign	Batten-Turner congenital myopathy	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358944	SCV001554801	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 611 of the CLCN1 protein (p.Arg611His). This variant is present in population databases (rs763850295, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 910973). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323800	SCV004028970	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1832G>A (p.Arg611His) 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 2.8e-05 in 251470 control chromosomes (i.e., 7 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1832G>A has been reported in the literature in at least two heterozygous individuals affected with Myotonia congenita, however without strong evidence for causality (e.g., Suetterlin_2022). This report therefore does not provide unequivocal conclusions about association of the variant with Myotonia congenita. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant does not affect the voltage dependence of activation in a manner in agreement with the variant being pathogenic, and behaves more similarly to the wild type in vitro (e.g., Suetterlin_2022). However, these findings do not allow convincing conclusions about the variant effect. The following publication was ascertained in the context of this evaluation (PMID: 34529042). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV004800707	SCV005421350	uncertain significance	not provided	2024-05-29	criteria provided, single submitter	clinical testing	Identified in patients with myotonia congenita in published literature, but familial segregation information and additional clinical information were not included (PMID: 34529042); Published functional studies suggest this variant has wild-type like activity, however additional studies are needed to validate the functional effect of this variant in vivo (PMID: 34529042); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34529042)