NM_000069.3(CACNA1S):c.3525+1G>A AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 25, 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:: RCV000809616.4

Allele description [Variation Report for NM_000069.3(CACNA1S):c.3525+1G>A]

NM_000069.3(CACNA1S):c.3525+1G>A

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.3525+1G>A

HGVS:

NC_000001.11:g.201059188C>T
NG_009816.2:g.58379G>A
NG_092961.1:g.352C>T
NM_000069.3:c.3525+1G>AMANE SELECT
NC_000001.10:g.201028316C>T
NM_000069.2:c.3525+1G>A

Links:

dbSNP: rs1572033599

NCBI 1000 Genomes Browser:

rs1572033599

Molecular consequence:

NM_000069.3:c.3525+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hypokalemic periodic paralysis, type 1
Synonyms:: HypoPP
Identifiers:: MONDO: MONDO:0042979; MedGen: C3714580; Orphanet: 681; OMIM: 170400

Name:: Malignant hyperthermia, susceptibility to, 5 (MHS5)
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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000949778	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 25, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 26247046, 28012042, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000949778

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 25, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing.

Hunter JM, Ahearn ME, Balak CD, Liang WS, Kurdoglu A, Corneveaux JJ, Russell M, Huentelman MJ, Craig DW, Carpten J, Coons SW, DeMello DE, Hall JG, Bernes SM, Baumbach-Reardon L.

Mol Genet Genomic Med. 2015 Jul;3(4):283-301. doi: 10.1002/mgg3.142. Epub 2015 Apr 8.

PubMed [citation]

PMID:: 26247046
PMCID:: PMC4521965

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000949778.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects a donor splice site in intron 27 of the CACNA1S gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CACNA1S are known to be pathogenic (PMID: 26247046, 28012042). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 653789). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 5, 2024

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