Submissions for variant NM_000083.3(CLCN1):c.1261C>T (p.Arg421Cys)

gnomAD frequency: 0.00001  dbSNP: rs756981034

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518336	SCV000612756	likely pathogenic	not provided	2017-03-23	criteria provided, single submitter	clinical testing
Invitae	RCV001857897	SCV002146734	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-09-19	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs756981034, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 22094069). 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. ClinVar contains an entry for this variant (Variation ID: 447047). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 22094069, 23113340, 23739125). This variant has been reported in individual(s) with autosomal dominant myotonia congenita (PMID: 23113340); however, the role of the variant in this condition is currently unclear. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 421 of the CLCN1 protein (p.Arg421Cys).
GeneDx	RCV000518336	SCV002538808	pathogenic	not provided	2022-06-22	criteria provided, single submitter	clinical testing	Reported in association with CLCN1-related myotonia congenita (Ivanova et al., 2012; Morrow et al., 2013); 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; Published functional studies demonstrate a damaging effect on channel current (Mazon et al., 2012; Suetterlin et al., 2021); This variant is associated with the following publications: (PMID: 31589614, 34529042, 23113340, 22094069, 23739125, 24349310, 23810313)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330738	SCV004038736	pathogenic	Congenital myotonia, autosomal recessive form	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1261C>T (p.Arg421Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251462 control chromosomes (gnomAD). c.1261C>T has been reported in the literature in multiple compound heterozygous individuals affected with Myotonia congenital (Mazon_2012, Brugnoni_2013, Suetterlin_2022). These data indicate that the variant is very likely to be associated with disease. At least one in vitro study reports this variant results in a reduction of the wild-type activity (Mazon_2012). The following publications have been ascertained in the context of this evaluation (PMID: 23739125, 22094069, 34529042). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.