Submissions for variant NM_000217.3(KCNA1):c.1126G>C (p.Gly376Arg)

dbSNP: rs1555085786

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522746	SCV000621980	uncertain significance	not provided	2017-10-31	criteria provided, single submitter	clinical testing	The G376R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G376R variant is not observed in large population cohorts (Lek et al., 2016). The G376R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. 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	RCV000709846	SCV005835983	likely pathogenic	Episodic ataxia type 1	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 376 of the KCNA1 protein (p.Gly376Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 453118). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNA1 protein function with a positive predictive value of 95%. This variant disrupts the p.Gly376 amino acid residue in KCNA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32705822; Internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GenomeConnect, ClinGen	RCV000709846	SCV000840177	not provided	Episodic ataxia type 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.