Submissions for variant NM_001127222.2(CACNA1A):c.1745G>A (p.Arg582Gln)

dbSNP: rs121908217

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517519	SCV000612509	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in individuals with familial hemiplegic migraine (FHM) and/or cerebellar ataxia (PMID: 24498617, 17142831, 11439943, 12707077). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant leads to altered calcium channel function (PMID: 10734061).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000517519	SCV001447183	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV001380080	SCV001578023	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-08-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 8505). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 10734061). 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 expected to disrupt CACNA1A protein function. This missense change has been observed in individuals with CACNA1A-related conditions (PMID: 12707077, 20837964, 24498617, 26814174). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121908217, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 583 of the CACNA1A protein (p.Arg583Gln).
Revvity Omics, Revvity	RCV000517519	SCV002018029	pathogenic	not provided	2021-08-16	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000517519	SCV002067465	pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227018	SCV002506544	pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 52	2022-03-20	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000009030	SCV002761927	pathogenic	Spinocerebellar ataxia type 6	2022-07-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000517519	SCV003845502	pathogenic	not provided	2023-03-22	criteria provided, single submitter	clinical testing	Published functional studies show that the R583Q variant affects the voltage-gated calcium ion channel (Kraus et al., 2000); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 12707077, 12056940, 18056581, 19624685, 22527033, 30078120, 32888184, 30710491, 32626992, 10408534, 23407676, 11439943, 10734061, 28717674, 25969684, 24498617, 28900389, 33084218, 26814174, 35401678)
Mayo Clinic Laboratories, Mayo Clinic	RCV000517519	SCV004225072	pathogenic	not provided	2023-04-19	criteria provided, single submitter	clinical testing	PP1, PP2, PP3, PS3, PS4
OMIM	RCV000009028	SCV000029244	pathogenic	Migraine, familial hemiplegic, 1	2003-04-01	no assertion criteria provided	literature only
OMIM	RCV000009029	SCV000029246	pathogenic	Sporadic hemiplegic migraine	2003-04-01	no assertion criteria provided	literature only
OMIM	RCV000009030	SCV000029247	pathogenic	Spinocerebellar ataxia type 6	2003-04-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009028	SCV000090841	not provided	Migraine, familial hemiplegic, 1		no assertion provided	not provided
GeneReviews	RCV001533158	SCV001748977	not provided	Familial hemiplegic migraine		no assertion provided	literature only
O&I group, Department of Genetics, University Medical Center of Groningen	RCV000009030	SCV001960824	pathogenic	Spinocerebellar ataxia type 6	2021-07-22	no assertion criteria provided	research