Submissions for variant NM_000083.3(CLCN1):c.2533G>A (p.Gly845Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317681	SCV004020382	uncertain significance	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.2533G>A (p.Gly845Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251496 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2533G>A has been reported in the literature once as a compound heterozygous genotype and once as an uninformative genotype (i.e. zygosity not specified) in individuals affected with Myotonia congenita (Ulzi_2012, Ferradini_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Myotonia congenita. At least one publication reports experimental evidence evaluating an impact of the variant on ion channel function and showed no damaging effect (Ulzi_2012). The following publications have been ascertained in the context of this evaluation (PMID: 28427807, 22521272). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV003883214	SCV004697562	uncertain significance	Congenital myotonia, autosomal recessive form	2024-02-20	criteria provided, single submitter	clinical testing