NM_000069.3(CACNA1S):c.3795G>T (p.Gln1265His) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Jun 22, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:

Allele description [Variation Report for NM_000069.3(CACNA1S):c.3795G>T (p.Gln1265His)]

NM_000069.3(CACNA1S):c.3795G>T (p.Gln1265His)

CACNA1S:calcium voltage-gated channel subunit alpha1 S [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000069.3(CACNA1S):c.3795G>T (p.Gln1265His)
  • NC_000001.11:g.201053459C>A
  • NG_009816.1:g.64108G>T
  • NG_009816.2:g.64108G>T
  • NM_000069.3:c.3795G>TMANE SELECT
  • NP_000060.2:p.Gln1265His
  • NC_000001.10:g.201022587C>A
  • NM_000069.2:c.3795G>T
Protein change:
dbSNP: rs201627041
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000069.3:c.3795G>T - missense variant - [Sequence Ontology: SO:0001583]


Hypokalemic periodic paralysis 1 (HOKPP1)
MONDO: MONDO:0042979; MedGen: C3714580; Orphanet: 681; OMIM: 170400
Malignant hyperthermia, susceptibility to, 5
Malignant hyperthermia susceptibility type 5; Malignant hyperpyrexia susceptibility type 5
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)
SCV001575382Invitaecriteria provided, single submitter
Likely pathogenic
(Jun 22, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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



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]

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Schartner V, Romero NB, Donkervoort S, Treves S, Munot P, Pierson TM, Dabaj I, Malfatti E, Zaharieva IT, Zorzato F, Abath Neto O, Brochier G, Lornage X, Eymard B, Taratuto AL, Böhm J, Gonorazky H, Ramos-Platt L, Feng L, Phadke R, Bharucha-Goebel DX, Sumner CJ, et al.

Acta Neuropathol. 2017 Apr;133(4):517-533. doi: 10.1007/s00401-016-1656-8. Epub 2016 Dec 23.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV001575382.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


This sequence change replaces glutamine with histidine at codon 1265 of the CACNA1S protein (p.Gln1265His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 30 of the CACNA1S coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201627041, ExAC 0.001%). This variant has been observed in combination with another CACNA1S variant in individual(s) with congenital myopathy (PMID: 26247046, 28012042). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 633684). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. 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.

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

Last Updated: Sep 23, 2021

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