NM_000069.3(CACNA1S):c.4113+1G>C AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Jun 12, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000687375.1

Allele description [Variation Report for NM_000069.3(CACNA1S):c.4113+1G>C]

NM_000069.3(CACNA1S):c.4113+1G>C

Gene:
CACNA1S:calcium voltage-gated channel subunit alpha1 S [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q32.1
Genomic location:
Preferred name:
NM_000069.3(CACNA1S):c.4113+1G>C
HGVS:
  • NC_000001.11:g.201050983C>G
  • NG_009816.1:g.66584G>C
  • NG_009816.2:g.66584G>C
  • NM_000069.3:c.4113+1G>CMANE SELECT
  • NC_000001.10:g.201020111C>G
  • NM_000069.2:c.4113+1G>C
Links:
dbSNP: rs1558056376
NCBI 1000 Genomes Browser:
rs1558056376
Molecular consequence:
  • NM_000069.3:c.4113+1G>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Hypokalemic periodic paralysis 1 (HOKPP1)
Synonyms:
HypoPP
Identifiers:
MONDO: MONDO:0042979; MedGen: C3714580; Orphanet: 681; OMIM: 170400
Name:
Malignant hyperthermia, susceptibility to, 5
Synonyms:
Malignant hyperthermia susceptibility type 5; Malignant hyperpyrexia susceptibility type 5
Identifiers:
MONDO: MONDO:0011163; MedGen: C1866077; Orphanet: 423; OMIM: 601887

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000814939Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 12, 2018)
germlineclinical testing

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

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, SCV000814939.1

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

Description

This sequence change affects a donor splice site in intron 33 of the CACNA1S gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1S-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1S are known to be pathogenic (PMID: 28012042). 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.

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

Last Updated: Oct 7, 2021

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