Submissions for variant NM_001127222.2(CACNA1A):c.6775C>T (p.Arg2259Trp)

dbSNP: rs750267834

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478520	SCV000571747	uncertain significance	not provided	2024-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001344534	SCV001538594	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2260 of the CACNA1A protein (p.Arg2260Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 422310). 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 not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. 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	RCV002367646	SCV002662422	uncertain significance	Inborn genetic diseases	2017-10-19	criteria provided, single submitter	clinical testing	The p.R2260W variant (also known as c.6778C>T), located in coding exon 46 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6778. The arginine at codon 2260 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000478520	SCV003830294	uncertain significance	not provided	2022-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479138	SCV004223577	uncertain significance	not specified	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.6778C>T (p.Arg2260Trp) 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 1e-05 in 198976 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.6778C>T in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003985367	SCV004786119	uncertain significance	CACNA1A-related disorder	2023-12-15	criteria provided, single submitter	clinical testing	The CACNA1A c.6775C>T variant is predicted to result in the amino acid substitution p.Arg2259Trp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13319575-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.