Submissions for variant NM_000083.3(CLCN1):c.1167-10T>C

gnomAD frequency: 0.00004  dbSNP: rs543120965

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000540290	SCV000636290	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the CLCN1 gene. It does not directly change the encoded amino acid sequence of the CLCN1 protein. This variant is present in population databases (rs543120965, gnomAD 0.003%). This variant has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 18337730, 22094069, 22649220, 23739125, 29606556). 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: 462828). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000711215	SCV000841547	likely pathogenic	not provided	2020-01-31	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. Not predicted to affect natural splicing. Low nucleotide conservation. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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.
Mendelics	RCV000987989	SCV001137532	likely pathogenic	Congenital myotonia, autosomal recessive form	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000711215	SCV001248206	likely pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000711215	SCV003826834	likely pathogenic	not provided	2022-10-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000987989	SCV003934131	pathogenic	Congenital myotonia, autosomal recessive form	2023-05-25	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1167-10T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a canonical 3' acceptor site. The variant allele was found at a frequency of 1.2e-05 in 251448 control chromosomes (gnomAD). c.1167-10T>C has been reported in the literature in multiple bi-allelic individuals affected with Myotonia congenita (examples: Trip_2008, Mazon_2012, Borklu-Yucel_2020, Orsini_2020). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 22094069, 18337730, 32117024). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000987989	SCV004697550	pathogenic	Congenital myotonia, autosomal recessive form	2024-02-20	criteria provided, single submitter	clinical testing