Submissions for variant NM_001127222.2(CACNA1A):c.6484G>A (p.Ala2162Thr)

dbSNP: rs17846928

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796072	SCV000935567	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-08-16	criteria provided, single submitter	clinical testing	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. 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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2163 of the CACNA1A protein (p.Ala2163Thr). This variant is not present in population databases (gnomAD no frequency). 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: 642583).
CeGaT Center for Human Genetics Tuebingen	RCV001531292	SCV001746321	likely benign	not provided	2021-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001531292	SCV001810855	likely benign	not provided	2021-07-28	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002534592	SCV003645358	likely benign	Inborn genetic diseases	2022-11-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Neuberg Centre For Genomic Medicine, NCGM	RCV003768490	SCV004697343	uncertain significance	Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing	The splice region c.4778-8C>A variant in CACNA1H gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This splice region variant in intron 26 affects the position nine nucleotides upstream of exon 27. Splice predictions do not report a damaging effect for this variant. For these reasons, this variant has been classified as Uncertain Significance (VUS).