Submissions for variant NM_000083.3(CLCN1):c.53G>T (p.Ser18Ile)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003052596	SCV003444218	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-11-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 18 of the CLCN1 protein (p.Ser18Ile). This variant is present in population databases (rs774525961, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2139436). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. 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.
Ambry Genetics	RCV003358064	SCV004053485	uncertain significance	Inborn genetic diseases	2023-07-17	criteria provided, single submitter	clinical testing	The c.53G>T (p.S18I) alteration is located in exon 1 (coding exon 1) of the CLCN1 gene. This alteration results from a G to T substitution at nucleotide position 53, causing the serine (S) at amino acid position 18 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994485	SCV004813036	uncertain significance	not specified	2024-02-28	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.53G>T (p.Ser18Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250996 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.53G>T in individuals affected with Congenital Myotonia, Autosomal Recessive Form and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2139436). Based on the evidence outlined above, the variant was classified as uncertain significance.