Submissions for variant NM_000083.3(CLCN1):c.2531T>C (p.Leu844Pro)

dbSNP: rs2116397538

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002004018	SCV002287702	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2021-06-17	criteria provided, single submitter	clinical testing	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 variant has been observed in individual(s) with clinical features of myotonia congenita (PMID: 18337100). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 844 of the CLCN1 protein (p.Leu844Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587289	SCV005075778	uncertain significance	not specified	2024-04-03	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.2531T>C (p.Leu844Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2531T>C has been reported in the literature in individuals affected with non-dystrophic myotonia in individuals with a heterozygous genotype or compound heterozygous genotype with reported autosomal dominant familial segregation of the alternate variant (e.g. Dupre_2009, Sasaki_2020). These reports do not provide unequivocal conclusions about association of the variant with Myotonia congenita. 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: 18337100, 32660787). ClinVar contains an entry for this variant (Variation ID: 1505353). Based on the evidence outlined above, the variant was classified as uncertain significance.