Submissions for variant NM_000083.3(CLCN1):c.697G>A (p.Gly233Ser)

dbSNP: rs139039122

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000991827	SCV001143601	pathogenic	not provided	2024-07-18	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in at least one compound heterozygous and at least one heterozygous individual with myotonia congenita. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 22790975) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000995507	SCV001149710	pathogenic	Congenital myotonia, autosomal recessive form	2019-11-11	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000995507	SCV002058472	pathogenic	Congenital myotonia, autosomal recessive form	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000804708, PMID:22790975, PS1_S). A different missense change at the same codon has been reported to be associated with CLCN1 related disorder (PMID:22094069, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.936, 3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Myotonia congenita (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002549767	SCV003440619	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 233 of the CLCN1 protein (p.Gly233Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with myotonia congenita (PMID: 22790975, 23113340, 29606556; Invitae). ClinVar contains an entry for this variant (Variation ID: 804708). 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"). Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22790975). 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.Gly233 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 22094069), which suggests that this may be a clinically significant amino acid residue. 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.
PreventionGenetics, part of Exact Sciences	RCV004528326	SCV004110759	likely pathogenic	CLCN1-related disorder	2023-07-25	criteria provided, single submitter	clinical testing	The CLCN1 c.697G>A variant is predicted to result in the amino acid substitution p.Gly233Ser. This variant was reported in the homozygous and compound heterozygous state in individuals with myotonia congenita (Suetterlin K et al 2022. PubMed ID: 34529042; Skálová et al. 2013. PubMed ID: 24349310;Table 1 in Ivanova et al. 2013. PubMed ID: 25438602; Stunnenberg et al. 2018. PubMed ID: 29606556; Table S1 in Suetterlin et al. 2022. PubMed ID: 34529042). The c.697G>A variant appears to be primarily associated with autosomal recessive myotonia congenita (Table 1 in Ivanova et al. 2013. PubMed ID: 25438602; Suetterlin et al. 2022. PubMed ID: 34529042); however, in one family it appears to possibly segregate with autosomal dominant mode of inheritance in a single family (Richman et al 2012. PubMed ID: 22790975). A different missense variant at this position (p.Gly233Val) has been reported with a CLCN1 frameshift variant in a patient with recessive myotonia congenita (Mazón et al 2012. PubMed ID: 22094069). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.