• replaced

NM_001127221.1(CACNA1A):c.3412C>G (p.Pro1138Ala) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Jun 1, 2018
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:
RCV000535498.3

Allele description

NM_001127221.1(CACNA1A):c.3412C>G (p.Pro1138Ala)

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_001127221.1(CACNA1A):c.3412C>G (p.Pro1138Ala)
HGVS:
  • NC_000019.10:g.13286647G>C
  • NG_011569.1:g.224814C>G
  • NM_000068.4:c.3421C>G
  • NM_001127221.1:c.3412C>G
  • NM_001127222.2:c.3409C>G
  • NM_001174080.2:c.3412C>G
  • NM_023035.3:c.3421C>G
  • NP_000059.3:p.Pro1141Ala
  • NP_001120693.1:p.Pro1138Ala
  • NP_001120694.1:p.Pro1137Ala
  • NP_001167551.1:p.Pro1138Ala
  • NP_075461.2:p.Pro1141Ala
  • LRG_7t1:c.3412C>G
  • LRG_7:g.224814C>G
  • LRG_7p1:p.Pro1138Ala
  • NC_000019.9:g.13397461G>C
  • NM_000068.2:c.3412C>G
Protein change:
P1137A
Links:
dbSNP: rs199793367
NCBI 1000 Genomes Browser:
rs199793367
Molecular consequence:
  • NM_000068.4:c.3421C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127221.1:c.3412C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127222.2:c.3409C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001174080.2:c.3412C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023035.3:c.3421C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Episodic ataxia type 2 (EA2)
Identifiers:
MedGen: C1720416; Orphanet: 97; OMIM: 108500
Name:
Epileptic encephalopathy, early infantile, 42 (EIEE42)
Identifiers:
MedGen: C4310716; OMIM: 617106

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000656751Invitae
criteria provided, single submitter

(Nykamp K et al. (Genet Med 2017))		Uncertain significance
(Jun 1, 2018) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000656751.3

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

Description

This sequence change replaces proline with alanine at codon 1138 of the CACNA1A protein (p.Pro1138Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs199793367, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 195471). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 2, 2019