Submissions for variant NM_000083.3(CLCN1):c.950G>A (p.Arg317Gln)

gnomAD frequency: 0.00001  dbSNP: rs80356702

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516960	SCV000612809	pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626585	SCV000747286	likely pathogenic	Migraine; Memory impairment; Muscle spasm; EMG: neuropathic changes; EMG: myotonic runs; Limb pain	2017-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763169	SCV000893758	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000763169	SCV000931840	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 317 of the CLCN1 protein (p.Arg317Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant and recessive myotonia congenita (PMID: 8533761, 10737121, 29606556; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17542). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 8845168).
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000019095	SCV001190886	likely pathogenic	Congenital myotonia, autosomal dominant form	2019-08-26	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000019094	SCV001369057	likely pathogenic	Congenital myotonia, autosomal recessive form	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PP3,PP2.
GeneDx	RCV000516960	SCV002044125	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in several families, but also in the heterozygous and homozygous state in one family with myotonia congenita (Meyer-Kleine et al., 1995; Esteban et al., 1998), and not observed in homozygous state in controls; Published functional studies indicate that R317Q shifts the gating threshold to a positive voltage thus altering channel gating and preventing repolarization of the channel (Pusch et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24349310, 25749817, 17395130, 12163078, 11933197, 15786415, 27415035, 9736777, 10737121, 8533761, 8845168, 34529042, 35907044)
Baylor Genetics	RCV000019094	SCV005049691	pathogenic	Congenital myotonia, autosomal recessive form	2024-02-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000019095	SCV005049859	pathogenic	Congenital myotonia, autosomal dominant form	2024-02-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000019094	SCV005400980	pathogenic	Congenital myotonia, autosomal recessive form	2023-06-22	criteria provided, single submitter	clinical testing	The observed missense c.950G>A (p.Arg317Gln) variant in CLCN1 gene has been reported in both homozygous and heterozygous states in multiple individuals affected with myotonia (Esteban et al., 1998; Meyer-Kleine et al., 1995; Stunnenberg et al., 2018). It has also been observed to segregate with disease in related individuals (Meyer-Kleine et al., 1995). Experimental studies indicate that p.Arg317Gln shifts the gating threshold to a positive voltage thus altering channel gating and preventing repolarization of the channel (Pusch et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg317Gln in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 317 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000019094	SCV000039382	pathogenic	Congenital myotonia, autosomal recessive form	1998-03-01	no assertion criteria provided	literature only
OMIM	RCV000019095	SCV000039383	pathogenic	Congenital myotonia, autosomal dominant form	1998-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000020121	SCV000040441	not provided	Batten-Turner congenital myopathy		no assertion provided	literature only
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000019095	SCV002549792	pathogenic	Congenital myotonia, autosomal dominant form	2022-04-06	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV000763169	SCV004228549	not provided	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-01-2019 by Lab 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.