Submissions for variant NM_000083.3(CLCN1):c.920T>C (p.Phe307Ser)

gnomAD frequency: 0.00004  dbSNP: rs80356701

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483128	SCV000567635	pathogenic	not provided	2022-09-02	criteria provided, single submitter	clinical testing	Reported in multiple unrelated families with myotonia congenita, in association with both autosomal dominant and autosomal recessive inheritance (Kubisch et al., 1998; Colding-Jorgensen et al., 2003; Fialho et al., 2007; Wang et al., 2022); Published functional studies demonstrate a shift in voltage dependence towards positive potentials, and the altered protein displayed a dominant-negative effect when expressed with wild type protein (Kubisch et al., 1998; Aromataris et al., 2001); Not observed at a 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, 11840191, 11408615, 17932099, 15162127, 12661046, 23152584, 23516313, 32010054, 32906206, 34529042, 35350395, 9736777)
Athena Diagnostics	RCV000483128	SCV000612804	pathogenic	not provided	2022-09-26	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 has been reported in multiple individuals with myotonia congenita together with a single recessive pathogenic variant in the same gene (PMID: 17932099, 12661046, 35350395), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 23516313, 23152584). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 11408615, 9736777.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000477848	SCV000759738	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CLCN1 protein (p.Phe307Ser). This variant is present in population databases (rs80356701, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 9736777, 17932099, 23152584, 23516313). 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: 21050). 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: 9736777, 11408615). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000020118	SCV000915213	pathogenic	Batten-Turner congenital myopathy	2018-11-18	criteria provided, single submitter	clinical testing	The CLCN1 c.920T>C (p.Phe307Ser) variant is a missense variant that has been reported in at least 12 unrelated individuals with myotonia congenita (Kubisch et al. 1998; Sun et al. 2001; Colding-Jorgensen et al. 2003; Fialho et al. 2007; Raheem et al. 2012; Horga et al. 2013). In the majority of cases, the variant acted in an autosomal dominant manner, but several of cases of compound heterozygosity and autosomal recessive inheritance were also reported. The p.Phe307Ser variant was absent from 50 controls but is reported at a frequency of 0.000155 in the European (Finnish) population of the Genome Aggregation Database. Functional studies in Xenopus oocytes showed a shifted voltage dependence of the variant channel that was expected to prevent efficient repolarization of the muscle action potential, a finding that has been seen with other disease-causing variants. (Kubisch et al. 1998; Aromataris et al. 2001). Based on the collective evidence, the p.Phe307Ser variant is classified as pathogenic for myotonia congenita. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Revvity Omics, Revvity	RCV000483128	SCV002019318	pathogenic	not provided	2019-10-10	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV002243656	SCV002515840	pathogenic	Congenital myotonia, autosomal dominant form	2022-04-20	criteria provided, single submitter	research	ACMG codes: PS4_Moderate, PS3, PM2, PP3
Baylor Genetics	RCV004562217	SCV005049688	pathogenic	Congenital myotonia, autosomal recessive form	2024-01-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002243656	SCV005049713	pathogenic	Congenital myotonia, autosomal dominant form	2024-01-24	criteria provided, single submitter	clinical testing
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477848	SCV000536752	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2016-05-12	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004541011	SCV004783743	pathogenic	CLCN1-related disorder	2024-04-01	no assertion criteria provided	clinical testing	The CLCN1 c.920T>C variant is predicted to result in the amino acid substitution p.Phe307Ser. This variant has been reported in multiple unrelated individuals and families with myotonia congenita (Kubisch et al. 1998. PubMed ID: 9736777; Sun et al. 2001. PubMed ID: 11840191; Fialho et al. 2007. PubMed ID: 17932099; Raheem et al. 2012. PubMed ID: 23152584; Horga et al. 2013. PubMed ID: 23516313). In most cases, this variant has displayed dominant inheritance but it has also been reported in the homozygous or compound heterozygous state with another pathogenic variant (Fialho et al. 2007. PubMed ID: 17932099; Horga et al. 2013. PubMed ID: 23516313). This variant is reported in 0.012% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic.