Submissions for variant NM_000083.3(CLCN1):c.2545G>A (p.Ala849Thr)

gnomAD frequency: 0.00030  dbSNP: rs201861334

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000368010	SCV000467132	likely benign	Batten-Turner congenital myopathy	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700433	SCV000829187	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2022-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 849 of the CLCN1 protein (p.Ala849Thr). This variant is present in population databases (rs201861334, gnomAD 0.05%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of CLCN1-related conditions (PMID: 31216405). ClinVar contains an entry for this variant (Variation ID: 359124). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics	RCV000711230	SCV000841562	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000700433	SCV000992750	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2012-10-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000711230	SCV001803633	uncertain significance	not provided	2024-03-03	criteria provided, single submitter	clinical testing	Previously reported as a variant of uncertain significance in the heterozygous state in a patient with Schinzel-Giedion syndrome who also harbored a de novo SETBP1 pathogenic variant (PMID: 25852444); 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: 31216405, 25852444)
Revvity Omics, Revvity	RCV000711230	SCV003830758	uncertain significance	not provided	2023-02-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000700433	SCV005667259	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-03-20	criteria provided, single submitter	clinical testing