Submissions for variant NM_000083.3(CLCN1):c.2285-1G>C

dbSNP: rs1222525763

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695019	SCV000823493	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2018-07-10	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 18 of the CLCN1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with myotonia congenita (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CLCN1 are known to be pathogenic (PMID: 17932099, 22094069, 23739125). For these reasons, this variant has been classified as Pathogenic.