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NM_001127222.2(CACNA1A):c.4175T>C (p.Val1392Ala) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Feb 28, 2021
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:
RCV002034426.5

Allele description

NM_001127222.2(CACNA1A):c.4175T>C (p.Val1392Ala)

Genes:
LOC126862864:MED14-independent group 3 enhancer GRCh37_chr19:13371552-13372751 [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.4175T>C (p.Val1392Ala)
HGVS:
  • NC_000019.10:g.13261525A>G
  • NG_011569.1:g.249936T>C
  • NM_000068.4:c.4187T>C
  • NM_001127221.2:c.4178T>C
  • NM_001127222.2:c.4175T>CMANE SELECT
  • NM_001174080.2:c.4178T>C
  • NM_023035.3:c.4187T>C
  • NP_000059.3:p.Val1396Ala
  • NP_001120693.1:p.Val1393Ala
  • NP_001120694.1:p.Val1392Ala
  • NP_001167551.1:p.Val1393Ala
  • NP_075461.2:p.Val1396Ala
  • LRG_7t1:c.4178T>C
  • LRG_7:g.249936T>C
  • NC_000019.9:g.13372339A>G
  • NM_001127221.1:c.4178T>C
Protein change:
V1392A
Links:
dbSNP: rs2144767386
NCBI 1000 Genomes Browser:
rs2144767386
Molecular consequence:
  • NM_000068.4:c.4187T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127221.2:c.4178T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127222.2:c.4175T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001174080.2:c.4178T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023035.3:c.4187T>C - 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
SCV002310889Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Feb 28, 2021) 		germlineclinical testing

PubMed (4)
[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

Missense mutations of CACNA1A are a frequent cause of autosomal dominant nonprogressive congenital ataxia.

Travaglini L, Nardella M, Bellacchio E, D'Amico A, Capuano A, Frusciante R, Di Capua M, Cusmai R, Barresi S, Morlino S, Fernández-Fernández JM, Trivisano M, Specchio N, Valeriani M, Vigevano F, Bertini E, Zanni G.

Eur J Paediatr Neurol. 2017 May;21(3):450-456. doi: 10.1016/j.ejpn.2016.11.005. Epub 2016 Nov 30.

PubMed [citation]
PMID:
28007337

Genetic landscape of pediatric movement disorders and management implications.

Cordeiro D, Bullivant G, Siriwardena K, Evans A, Kobayashi J, Cohn RD, Mercimek-Andrews S.

Neurol Genet. 2018 Oct;4(5):e265. doi: 10.1212/NXG.0000000000000265.

PubMed [citation]
PMID:
30283815
PMCID:
PMC6167181
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV002310889.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val1393 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28007337, 30283815, 31468518). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 variant has not been reported in the literature in individuals with CACNA1A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with alanine at codon 1393 of the CACNA1A protein (p.Val1393Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine.

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

Last Updated: May 26, 2024