ClinVar Miner

Submissions for variant NM_004366.6(CLCN2):c.335T>C (p.Ile112Thr)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002299653 SCV002589182 uncertain significance not provided 2022-08-30 criteria provided, single submitter clinical testing 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. 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) performed at Invitae indicates that this missense variant is expected to disrupt CLCN2 protein function. This variant has not been reported in the literature in individuals affected with CLCN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 112 of the CLCN2 protein (p.Ile112Thr).
Neuberg Centre For Genomic Medicine, NCGM RCV002510601 SCV002820144 uncertain significance Epilepsy, idiopathic generalized, susceptibility to, 11 criteria provided, single submitter clinical testing The missense variant c.335T>C (p.Ile112Thr) in CLCN2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ile112Thr variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ile at position 112 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ile112Thr in CLCN2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.

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