Submissions for variant NM_000083.3(CLCN1):c.696G>A (p.Glu232=)

dbSNP: rs923380712

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484576	SCV000570160	uncertain significance	not provided	2017-05-25	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CLCN1 gene. The c.696 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.696 G>A may damage or destroy the natural splice donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000807571	SCV000947633	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2018-08-05	criteria provided, single submitter	clinical testing	Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has not been reported in the literature in individuals with CLCN1-related disease. ClinVar contains an entry for this variant (Variation ID: 421069). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 232 of the CLCN1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CLCN1 protein. This variant also falls at the last nucleotide of exon 5 of the CLCN1 coding sequence, which is part of the consensus splice site for this exon. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000484576	SCV001155290	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing