Submissions for variant NM_000083.3(CLCN1):c.1357C>T (p.Arg453Trp)

gnomAD frequency: 0.00011  dbSNP: rs376026619

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484220	SCV000568786	uncertain significance	not provided	2017-01-04	criteria provided, single submitter	clinical testing	The R453W variant in the CLCN1 gene has been reported along with a second variant in the CLCN1 gene in an individual with myotonia, muscle stiffness, fatigue, muscle cramps, myalgia, generalized muscular hypertrophy with worsening of symptoms in cold temperatures (Portaro et al., 2015). However, functional studies demonstrated that the chloride current in cells transfected with the R453W variant was similar to wild-type (Portaro et al., 2015). The R453W variant was not observed at a significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R453W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. We interpret R453W as a variant of uncertain significance.
Invitae	RCV000536748	SCV000636304	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 453 of the CLCN1 protein (p.Arg453Trp). This variant is present in population databases (rs376026619, gnomAD 0.08%). This missense change has been observed in individual(s) with clinical features of myotonia congenita (PMID: 26007199; 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: 420148). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect CLCN1 function (PMID: 26007199). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Revvity Omics, Revvity	RCV000484220	SCV003830753	uncertain significance	not provided	2022-09-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155206	SCV003844670	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1357C>T (p.Arg453Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CLCN1 causing Myotonia congenita (8e-05 vs 0.0035), allowing no conclusion about variant significance. c.1357C>T has been reported in the literature in individuals affected with Myotonia congenita (e.g. Brugnoni_2013, Portaro_2015). These data do not allow any conclusion about variant significance. Transient expression in tsA201 cells show the variant had similar activity as WT (Portaro_2015), indicating no chance in function. The following publications have been ascertained in the context of this evaluation (PMID: 23739125, 26007199). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.