Submissions for variant NM_000083.3(CLCN1):c.1863A>G (p.Thr621=)

gnomAD frequency: 0.00001  dbSNP: rs369099862

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000609340	SCV000724680	likely benign	not specified	2017-11-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001041504	SCV001205125	likely benign	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-04-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001163172	SCV001325183	likely benign	Batten-Turner congenital myopathy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GenomeConnect - Invitae Patient Insights Network	RCV001041504	SCV001749707	not provided	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 04-02-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004737890	SCV005366508	uncertain significance	CLCN1-related disorder	2024-03-11	no assertion criteria provided	clinical testing	The CLCN1 c.1863A>G variant is not predicted to result in an amino acid change (p.=). This silent variant is predicted to create a new splicing site based on available splicing prediction programs (Alamut Visual Plus v1.6.1). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.