Submissions for variant NM_000083.3(CLCN1):c.1283T>C (p.Phe428Ser)

gnomAD frequency: 0.00003  dbSNP: rs774843953

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518351	SCV000612759	pathogenic	not provided	2019-02-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701519	SCV000830322	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 428 of the CLCN1 protein (p.Phe428Ser). This variant is present in population databases (rs774843953, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive myotonia congenita (internal data). 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: 208083). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 12390967). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000518351	SCV002770228	likely pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Reported previously in a patient with a clinical diagnosis of paramyotonia congenita including muscle stiffness, hand weakness and paraesthesias, and abnormal EMG (Wu et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12390967, 15786415, 9040658, 20301529, 22187529, 22507243, Prado2020[CaseReport])
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV003313944	SCV004013263	likely pathogenic	Congenital myotonia, autosomal recessive form	2023-06-01	criteria provided, single submitter	clinical testing	PS3_Supporting, PM2, PM3, PP3
Fulgent Genetics, Fulgent Genetics	RCV000701519	SCV005667238	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-04-22	criteria provided, single submitter	clinical testing
GeneReviews	RCV000193137	SCV000243884	not provided	Batten-Turner congenital myopathy		no assertion provided	literature only
Eurofins Ntd Llc (ga)	RCV000518351	SCV000858401	uncertain significance	not provided	2017-11-28	flagged submission	clinical testing
Revvity Omics, Revvity	RCV000518351	SCV003830766	uncertain significance	not provided	2019-05-31	flagged submission	clinical testing