Submissions for variant NM_000083.3(CLCN1):c.991G>T (p.Ala331Ser)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003782655	SCV004604425	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-07-24	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 34529042). 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. This missense change has been observed in individual(s) with clinical features of myotonia congenita (PMID: 34529042; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 331 of the CLCN1 protein (p.Ala331Ser).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004527008	SCV005039276	likely pathogenic	Congenital myotonia, autosomal recessive form	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.991G>T (p.Ala331Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.991G>T has been reported in the literature in at-least one individuals affected with autosomal recessive Myotonia congenita (Suetterlin_2022). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in reduced rates of activation and a right-shift hyperpolarizing pre-pulse comparing to WT CLCN1 channel when expressed in Xenopus oocytes (Suetterlin_2022). The following publication have been ascertained in the context of this evaluation (PMID: 34529042). ClinVar contains an entry for this variant (Variation ID: 2921633). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004542250	SCV005040832	likely pathogenic	Metachromatic leukodystrophy	2024-03-21	criteria provided, single submitter	clinical testing	Variant summary: ARSA c.991G>T (p.Glu331X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 212420 control chromosomes (gnomAD). c.991G>T has been reported in the literature in at least an individual affected with Metachromatic Leukodystrophy (Bertelli_2005). These data do not allow any conclusion about variant significance. ARSA activity from patient (who was compound heterozygous for the variant) derived leukocytes was found to be 6.7nm/h/mg (Bertelli_2005). One ClinVar submitter (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.