Submissions for variant NM_000083.3(CLCN1):c.1592C>T (p.Ala531Val)

gnomAD frequency: 0.00001  dbSNP: rs80356704

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638249	SCV000759735	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 531 of the CLCN1 protein (p.Ala531Val). This variant is present in population databases (rs80356704, gnomAD 0.04%). This missense change has been observed in individual(s) with myotonia congenita (PMID: 10430417, 11840191, 21221019, 22094069, 23933576; Invitae). 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: 21040). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 17990293, 23424641, 23933576, 26021757, 27580824). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000711222	SCV000841554	pathogenic	not provided	2018-04-24	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000711222	SCV001715973	pathogenic	not provided	2019-07-07	criteria provided, single submitter	clinical testing	PS3, PS4_moderate, PM3, PP1, PP3
Fulgent Genetics, Fulgent Genetics	RCV000638249	SCV002811023	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267607	SCV004020372	pathogenic	Congenital myotonia, autosomal recessive form	2023-06-23	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1592C>T (p.Ala531Val) 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 allele was found at a frequency of 4.4e-05 in 251370 control chromosomes, exclusively at a frequency of 4.4e-05 (i.e., 11 heterozygotes) within the Finnish subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1592C>T has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Myotonia, Autosomal Recessive Form (e.g., Sun_2002, Modoni_2011). Additionally, the variant was identified in several apparent heterozygotes affected with myotonia and latent myotonia, but was observed in unaffected heterozygous carriers as well, suggesting this variant may also cause autosomal dominant disease although with reduced penetrance (e.g., Sun_2002). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21221019, 11840191). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002267607	SCV004697554	pathogenic	Congenital myotonia, autosomal recessive form	2024-02-20	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020102	SCV000040422	not provided	Batten-Turner congenital myopathy		no assertion provided	literature only	Associated with autosomal recessive and autosomal dominant mode of inheritance
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267607	SCV002549783	pathogenic	Congenital myotonia, autosomal recessive form	2022-04-06	no assertion criteria provided	research