Submissions for variant NM_001127222.2(CACNA1A):c.6679C>T (p.Arg2227Cys)

gnomAD frequency: 0.00001  dbSNP: rs757715357

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478540	SCV000574366	uncertain significance	not provided	2017-03-24	criteria provided, single submitter	clinical testing	The R2228C variant in the CACNA1A gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is observed in 2/7476 (0.03%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016).] The R2228C 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 where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R2228C as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001241367	SCV001414381	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-07-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2228 of the CACNA1A protein (p.Arg2228Cys). This variant is present in population databases (rs757715357, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 424549). 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 CACNA1A 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.
CeGaT Center for Human Genetics Tuebingen	RCV000478540	SCV004137974	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	CACNA1A: PP2, PP3