Submissions for variant NM_000083.3(CLCN1):c.689G>A (p.Gly230Glu)

dbSNP: rs80356700

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000291823	SCV000329298	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing	Reported previously in multiple unrelated families with myotonia congenita, most often in association with autosomal dominant inheritance (George et al., 1993; Meyer-Kleine et al., 1995).; Reported in a family exhibiting autosomal dominant inheritance, at least one carrier of G230E variant was reported to be clinically unaffected in adulthood, although EMG revealed subclinical myotonia (Meyer-Kleine et al., 1995).; Published functional studies have demonstrated that the Gly230 residue resides within the chloride channel pore and the G230E variant dramatically alters pore properties (Fahlke et al., 1997); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 10467912, 10533075, 15786415, 23739125, 28427807, 7981750, 8857733, 10720929, 11933197, 12390967, 18220014, 24349310, 18263754, 19570891, 9122265, 8857727, 8533761, 20301529, 29424939, 29606556, 31692161, 32670189)
Athena Diagnostics Inc	RCV000291823	SCV000612794	pathogenic	not provided	2023-01-09	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 is associated with autosomal dominant myotonia congenita in most families (PMID: 10533075, 8857727, 7981750, 18220014, 10467912, 23516313), however, it has also been associated with autosomal recessive myotonia congenita (PMID: 8857733, 23516313). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9122265, 8112288)
Invitae	RCV000627758	SCV000649787	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 230 of the CLCN1 protein (p.Gly230Glu). This variant is present in population databases (rs80356700, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal dominant myotonia congenita (PMID: 7981750, 18220014). It has also been observed to segregate with disease in related individuals. This variant is also known as Gly180Glu. ClinVar contains an entry for this variant (Variation ID: 17532). 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%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 8112288, 9122265). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000627758	SCV000893755	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-03-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000291823	SCV001715969	pathogenic	not provided	2020-09-25	criteria provided, single submitter	clinical testing	PS3, PS4, PP1, PP3, PP4
Revvity Omics, Revvity	RCV000291823	SCV002019337	pathogenic	not provided	2023-10-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000019084	SCV002038563	pathogenic	Congenital myotonia, autosomal dominant form	2021-05-12	criteria provided, single submitter	clinical testing	The CLCN1 c.689G>A (p.Gly230Glu) variant is a missense variant. Across a selection of the available literature, the p.Gly230Glu variant has been identified in a heterozygous state in at least eight probands and 12 affected family members with autosomal dominant myotonia congenita from eight families showing segregation with the disorder (George et al. 1993; Koty et al. 1996; Brugnoni et al. 1999, Chang et al. 2015). Expressivity of the disease associated with the variant is variable, Chang et al. (2015) reported the variant to be present in a heterozygous state in one 17-year-old female asymptomatic carrier in a family with two affected individuals. The p.Gly230Glu variant was also reported in a compound heterozygous state with a stop gained variant in one individual, in whose family both the mother and sibling were noted to be carriers of the p.Gly230Glu variant and asymptomatic (Zhang et al. 1996). The p.Gly230Glu variant is reported at a frequency of 0.000012 in the total population of the Genome Aggregation Database (version 2.1.1) in a region of good sequence coverage. Heterologous expression of the p.Gly230Glu variant in Xenopus oocytes suggest the variant exerts a dominant negative effect on the channel. Additional work in mammalian cell lines showed that the p.Gly230Glu variant induced changes in ion selectivity relative to the wildtype protein (Steinmeyer et al. 1994; Fahlke et al. 1997). Based on the collective evidence and application of the ACMG criteria, the p.Gly230Glu variant is classified as pathogenic for the autosomal dominant form of myotonia congenita.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317041	SCV004020403	pathogenic	Congenital myotonia, autosomal recessive form	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.689G>A (p.Gly230Glu) results in a non-conservative amino acid change located in the TM1 domain (Sutterlin_2022) of 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 1.2e-05 in 251000 control chromosomes. c.689G>A has been reported in the literature as a heterozygous genotype or as a compound heterozygous genotype in multiple individuals affected with Congenital Myotonia (example, Sutterlin_2022; Horga_2013). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Fahlke_1997, Steinmeyer_1994). The most pronounced variant effect results in altered pore properties of the muscle chloride channel (Fahle_1997) and destroy normal channel activity while exerting a dominant negative effect of wild-type channels (Steinmeyer_1994). The following publications have been ascertained in the context of this evaluation (PMID: 9122265, 23516313, 8112288, 34529042). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003904849	SCV004726910	pathogenic	CLCN1-related condition	2024-02-12	criteria provided, single submitter	clinical testing	The CLCN1 c.689G>A variant is predicted to result in the amino acid substitution p.Gly230Glu. This variant has been previously reported in multiple families with myotonia congenita, primarily in association with autosomal dominant inheritance (George et al. 1993. PubMed ID: 7981750; Meyer-Kleine et al. 1995. PubMed ID: 8533761; Chang et al. 2007. PubMed ID: 18220014). Functional studies suggested that the p.Gly230Glu substitution dramatically altered the pore properties of CLCN1 (Fahlke et al. 1997. PMID: 9122265). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.
OMIM	RCV000019084	SCV000039372	pathogenic	Congenital myotonia, autosomal dominant form	1997-03-18	no assertion criteria provided	literature only
GeneReviews	RCV000020113	SCV000040433	not provided	Batten-Turner congenital myopathy		no assertion provided	literature only	Associated with autosomal recessive and autosomal dominant mode of inheritance
GenomeConnect - Invitae Patient Insights Network	RCV000627758	SCV001749973	not provided	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 03-09-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.