Submissions for variant NM_000083.3(CLCN1):c.871G>A (p.Glu291Lys)

gnomAD frequency: 0.00001  dbSNP: rs121912805

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001041229	SCV001204831	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 291 of the CLCN1 protein (p.Glu291Lys). This variant is present in population databases (rs121912805, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8845168, 23739125, 27415035). 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: 17541). 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: 8845168). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001781282	SCV002023246	likely pathogenic	not provided	2021-10-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001781282	SCV002575339	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in loss of channel activity in a recessive manner (Pusch et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11933197, 24349310, 34790634, 10508236, 34142127, 11137655, 19185184, 9736777, 8845168, 8533761, 23739125, 35170402, 27415035, 28662944, 32660787)
MGZ Medical Genetics Center	RCV000019093	SCV002581039	likely pathogenic	Congenital myotonia, autosomal recessive form	2022-07-12	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002468557	SCV002764976	pathogenic	Congenital myotonia, autosomal dominant form	2020-11-09	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV002468557	SCV004809649	pathogenic	Congenital myotonia, autosomal dominant form	2024-04-04	criteria provided, single submitter	clinical testing
OMIM	RCV000019093	SCV000039381	pathogenic	Congenital myotonia, autosomal recessive form	2019-06-21	no assertion criteria provided	literature only