Submissions for variant NM_001127222.2(CACNA1A):c.4034G>A (p.Arg1345Gln)

dbSNP: rs121908230

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516653	SCV000612537	pathogenic	not provided	2022-11-22	criteria provided, single submitter	clinical testing	This variant segregates with hemiplegic migraine with progressive cerebellar ataxia in at least one family and has also been seen in at least one de novo case. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
CeGaT Center for Human Genetics Tuebingen	RCV000516653	SCV001248620	pathogenic	not provided	2019-07-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000516653	SCV001447587	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000516653	SCV002552987	likely pathogenic	not provided	2022-01-12	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; This variant is associated with the following publications: (PMID: 27435762, 15032980, 29482223, 33790770)
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795386	SCV005415799	pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing	PM2_Supporting+PP2+PS4+PM6+PP1_Moderate+PP3_Strong+PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222676	SCV005863226	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1346 of the CACNA1A protein (p.Arg1346Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 19811514). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8513). 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 CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000009039	SCV000029256	pathogenic	Migraine, familial hemiplegic, 1	2008-11-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009039	SCV000090852	not provided	Migraine, familial hemiplegic, 1		no assertion provided	not provided
Solve-RD Consortium	RCV004766990	SCV005091511	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team