Submissions for variant NM_001127222.2(CACNA1A):c.6505C>T (p.Arg2169Cys)

gnomAD frequency: 0.00022  dbSNP: rs375354077

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000732133	SCV000571342	uncertain significance	not provided	2016-08-15	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CACNA1A gene. The R2170C variant has not beenpublished as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. Although theR2170C was not observed with any significant frequency in approximately 6,000 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, the data was noted to have reduced depth of sequencingreads and therefore may be unreliable. The R2170C variant is a non-conservative amino acid substitution, which islikely 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 isprobably damaging to the protein structure/function. However, missense variants in nearby residues have not beenreported in the Human Gene Mutation Database in association with CACNA1A-related disorders (Stenson et al.,2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenicvariant or a rare benign variant.
Invitae	RCV001087818	SCV000656791	likely benign	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002311805	SCV000847338	uncertain significance	Inborn genetic diseases	2016-07-25	criteria provided, single submitter	clinical testing	The p.R2170C variant (also known as c.6508C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6508. The arginine at codon 2170 is replaced by cysteine, an amino acid with highly 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.
Eurofins Ntd Llc (ga)	RCV000732133	SCV000860043	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764175	SCV000895177	uncertain significance	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2018-10-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000732133	SCV001143345	likely benign	not provided	2020-04-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003985362	SCV004762820	likely benign	CACNA1A-related disorder	2023-02-22	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).