Submissions for variant NM_000083.3(CLCN1):c.962T>A (p.Val321Glu)

dbSNP: rs780150093

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000800361	SCV000940071	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 321 of the CLCN1 protein (p.Val321Glu). This variant is present in population databases (rs780150093, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 34790634, 35350395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 646134). 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%. For these reasons, this variant has been classified as Pathogenic.
The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University	RCV001836890	SCV001786714	likely pathogenic	Batten-Turner congenital myopathy	2021-08-15	criteria provided, single submitter	clinical testing