Submissions for variant NM_001127222.2(CACNA1A):c.575G>A (p.Arg192Gln)

dbSNP: rs121908211

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512926	SCV003443219	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-02-11	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 192 of the CACNA1A protein (p.Arg192Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with epileptic encephalopathy with cerebellar atrophy and Familial hemiplegic migraine (PMID: 8898206; Invitae). ClinVar contains an entry for this variant (Variation ID: 8487). 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. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 10024348, 19242091, 25716839). This variant disrupts the p.Arg192 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1A-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV003231095	SCV003930261	pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R192Q results in a gain of function effect on the calcium channel function (van den Maagdenberg et al., 2004; Magni et al., 2019); Variant previously reported in affected individuals in a family with familial hemiplegic migraine (Ophoff et al., 1996); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25481823, 24583041, 31260335, 23985897, 19242091, 22144569, 22956801, 10024348, 25716839, 9488686, 19104150, 20735819, 18581134, 22836594, 26208839, 30080864, 15003170, 8898206)
OMIM	RCV000009008	SCV000029222	pathogenic	Migraine, familial hemiplegic, 1	1996-11-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009008	SCV000090869	not provided	Migraine, familial hemiplegic, 1		no assertion provided	not provided
GeneReviews	RCV001533156	SCV001748975	not provided	Familial hemiplegic migraine		no assertion provided	literature only	Hemiplegic attacks