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NM_001127222.2(CACNA1A):c.575G>A (p.Arg192Gln) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 11, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002512926.3

Allele description [Variation Report for NM_001127222.2(CACNA1A):c.575G>A (p.Arg192Gln)]

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

Gene:
CACNA1A:calcium voltage-gated channel subunit alpha1 A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19p13.13
Genomic location:
Preferred name:
NM_001127222.2(CACNA1A):c.575G>A (p.Arg192Gln)
HGVS:
  • NC_000019.10:g.13371744C>T
  • NG_011569.1:g.139717G>A
  • NM_000068.4:c.575G>A
  • NM_001127221.2:c.575G>A
  • NM_001127222.2:c.575G>AMANE SELECT
  • NM_001174080.2:c.575G>A
  • NM_023035.3:c.575G>A
  • NP_000059.3:p.Arg192Gln
  • NP_001120693.1:p.Arg192Gln
  • NP_001120693.1:p.Arg192Gln
  • NP_001120694.1:p.Arg192Gln
  • NP_001167551.1:p.Arg192Gln
  • NP_075461.2:p.Arg192Gln
  • LRG_7t1:c.575G>A
  • LRG_7:g.139717G>A
  • LRG_7p1:p.Arg192Gln
  • NC_000019.9:g.13482558C>T
  • NM_001127221.1:c.575G>A
Protein change:
R192Q; ARG192GLN
Links:
UniProtKB/Swiss-Prot: VAR_001491; OMIM: 601011.0001; dbSNP: rs121908211
NCBI 1000 Genomes Browser:
rs121908211
Molecular consequence:
  • NM_000068.4:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127221.2:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127222.2:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001174080.2:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023035.3:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Episodic ataxia type 2 (EA2)
Synonyms:
Episodic ataxia with nystagmus; Nystagmus-associated episodic ataxia; Cerebellopathy, hereditary paroxysmal; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0007163; MedGen: C1720416; Orphanet: 97; OMIM: 108500
Name:
Developmental and epileptic encephalopathy, 42 (DEE42)
Synonyms:
Epileptic encephalopathy, early infantile, 42
Identifiers:
MONDO: MONDO:0014917; MedGen: C4310716; OMIM: 617106

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003443219Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 11, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.

Ophoff RA, Terwindt GM, Vergouwe MN, van Eijk R, Oefner PJ, Hoffman SM, Lamerdin JE, Mohrenweiser HW, Bulman DE, Ferrari M, Haan J, Lindhout D, van Ommen GJ, Hofker MH, Ferrari MD, Frants RR.

Cell. 1996 Nov 1;87(3):543-52.

PubMed [citation]
PMID:
8898206

Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine.

Hans M, Luvisetto S, Williams ME, Spagnolo M, Urrutia A, Tottene A, Brust PF, Johnson EC, Harpold MM, Stauderman KA, Pietrobon D.

J Neurosci. 1999 Mar 1;19(5):1610-9.

PubMed [citation]
PMID:
10024348
PMCID:
PMC6782159
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443219.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024