Submissions for variant NM_000083.3(CLCN1):c.892G>A (p.Ala298Thr)

gnomAD frequency: 0.00002  dbSNP: rs764100025

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638241	SCV000759727	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-12-31	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 28706458). 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. ClinVar contains an entry for this variant (Variation ID: 531747). This missense change has been observed in individuals with autosomal dominant myotonia congenita (MC) (PMID: 21045501, 27118449, 27415035, 28706458). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs764100025, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 298 of the CLCN1 protein (p.Ala298Thr).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761298	SCV000891273	likely pathogenic	Congenital myotonia, autosomal dominant form	2016-06-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000991830	SCV001143604	pathogenic	not provided	2021-08-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been reported as autosomal dominant myotonia congenita (PMID: 27415035, 21045501), and has also been reported as autosomal recessive myotonia congenita (PMID: 27118449). This variant segregates with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. Study shows this variant results in altered channel properties (PMID:28706458).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000761298	SCV005381410	pathogenic	Congenital myotonia, autosomal dominant form	2024-08-05	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.892G>A (p.Ala298Thr) 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 1.6e-05 in 251390 control chromosomes. c.892G>A has been reported in the literature in in the heterozygous and compound heterozygous states in multiple individuals affected with autosomal dominant and autosomal recessive myotonia congenita and segregated with disease in at least two families (e.g. Yang_2017, Chin_2017, Sasaki_2020, Meng_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant results in reduced chloride current density and altered channel gating compared to wildtype in vitro (e.g. Chin_2017). The following publications have been ascertained in the context of this evaluation (PMID: 28706458, 27118449, 32660787, 27415035). ClinVar contains an entry for this variant (Variation ID: 531747). Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000991830	SCV005413811	pathogenic	not provided	2024-04-08	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PS3_moderate, PS4_moderate
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000638241	SCV005416428	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PP1_Strong+PP4+PP3_Moderate
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267619	SCV002549781	pathogenic	Congenital myotonia, autosomal recessive form	2022-04-06	no assertion criteria provided	research
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV000761298	SCV002549790	pathogenic	Congenital myotonia, autosomal dominant form	2022-04-06	no assertion criteria provided	research