Submissions for variant NM_000083.3(CLCN1):c.1650G>A (p.Thr550=)

gnomAD frequency: 0.00003  dbSNP: rs778647317

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047235	SCV001211175	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change affects codon 550 of the CLCN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs778647317, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 23516313, 31772215). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 844401). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323787	SCV004028949	pathogenic	Congenital myotonia, autosomal recessive form	2023-07-26	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1650G>A alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: four predict the variant strengthens a cryptic 5' donor site, and two predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251232 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1650G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Myotonia congenita, and the variant has been shown to segregate with disease in related individuals (e.g., Horga_2013). The variant has also been suggested to be a modifier of disease in a heterozygous patient with myotonia who also harbored a heterozygous SCN4A variant (e.g., Thor_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23516313, 31772215). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.