Submissions for variant NM_000083.3(CLCN1):c.1013G>A (p.Arg338Gln)

gnomAD frequency: 0.00003  dbSNP: rs80356703

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517885	SCV000612750	pathogenic	not provided	2022-12-28	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 statistically more frequent in affected individuals than in the general population and/or healthy controls. This variant has been reported in multiple individuals with a single recessive pathogenic variant in the same gene, suggesting it is associated with autosomal recessive myotonia congenita (PMID: 18337100, 27415035, 33263785, 7874130), however, it has also been reported in a family with possible autosomal dominant myotonia congenita (PMID: 8857733). Assessment of experimental evidence suggests this variant results in abnormal protein function. The mutant protein caused a right-shift in the voltage-dependent of channel activation (PMID: 10690989).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638255	SCV000759742	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-02-23	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 338 of the CLCN1 protein (p.Arg338Gln). This variant is present in population databases (rs80356703, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 7874130, 8857733, 12390967, 18337100, 23739125, 27415035; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 21037). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10690989). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000517885	SCV002019321	pathogenic	not provided	2023-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000517885	SCV002574632	likely pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant impairs normal muscle excitability (Zhang et al., 2000); 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: 15786415, 34426522, 7874130, 22187529, 11933197, 11840191, 31589614, 10690989, 10619717, 23739125, 18337100, 8533761, 18263754, 15311340, 18816629, 22521272, 29606556, 12390967, 32010054, 27415035, 8857733, 33263785)
Fulgent Genetics, Fulgent Genetics	RCV000638255	SCV002809799	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2021-09-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003322591	SCV004027781	pathogenic	Congenital myotonia, autosomal dominant form	2023-06-05	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PM1,PM3,PS4_SUP,PP4
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335049	SCV004046216	pathogenic	CLCN1-related disorder		criteria provided, single submitter	clinical testing	This variant has been reported in the compound heterozygous state in individuals affected with autosomal recessive myotonia congenita (PMID: 7874130, 27415035) and also in individuals with autosomal dominant myotonia congenita (PMID: 8857733, 23739125). This variant has been described to show variable modes of transmission in different families including incomplete dominance and incomplete penetrance (20301529, 8857733, 12390967, 18337100). Functional studies in cultured muscle cells have shown that this missense change alters the properties of the CLCN1 chloride channel, which is thought to affect its ability to maintain normal muscle excitability (PMID: 10690989). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (8/282872) and thus is presumed to be rare. This variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1013G>A (p.Arg338Gln) variant is classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338385	SCV004047351	pathogenic	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	clinical testing	The CLCN1 c.1013G>A (p.Arg338Gln) variant has been reported with a second CLCN1 variant in individuals affected with autosomal recessive myotonia congenita (Yang X et al., 2016). Experimental studies has shown that this missense change alters the properties of the CLCN1 chloride channel in cell culture (Zhang J et al). This variant is reported with the allele frequency (0.0028%) in the gnomad and novel in 1000 genome database. It has been submitted to ClinVar as Pathogenic. The amino acid Arg at position 338 is changed to a Gln changing protein sequence and it might alter its composition and physicochemical properties. The amino acid change p.Arg338Gln in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.