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NM_001127222.2(CACNA1A):c.4999C>T (p.Leu1667Phe) AND multiple conditions

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 21, 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:
RCV002028613.5

Allele description

NM_001127222.2(CACNA1A):c.4999C>T (p.Leu1667Phe)

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.4999C>T (p.Leu1667Phe)
HGVS:
  • NC_000019.10:g.13235682G>A
  • NG_011569.1:g.275779C>T
  • NM_000068.4:c.5017C>T
  • NM_001127221.2:c.5002C>T
  • NM_001127222.2:c.4999C>TMANE SELECT
  • NM_001174080.2:c.5008C>T
  • NM_023035.3:c.5017C>T
  • NP_000059.3:p.Leu1673Phe
  • NP_001120693.1:p.Leu1668Phe
  • NP_001120694.1:p.Leu1667Phe
  • NP_001167551.1:p.Leu1670Phe
  • NP_075461.2:p.Leu1673Phe
  • LRG_7:g.275779C>T
  • NC_000019.9:g.13346496G>A
Protein change:
L1667F
Links:
dbSNP: rs2144649806
NCBI 1000 Genomes Browser:
rs2144649806
Molecular consequence:
  • NM_000068.4:c.5017C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127221.2:c.5002C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127222.2:c.4999C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001174080.2:c.5008C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_023035.3:c.5017C>T - 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
SCV002277742Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Uncertain significance
(Mar 21, 2021) 		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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV002277742.3

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

Description

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. 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 leucine with phenylalanine at codon 1668 of the CACNA1A protein (p.Leu1668Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine.

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

Last Updated: Mar 5, 2024