ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.3795G>T (p.Gln1265His) (rs201627041)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001377927 SCV001575382 likely pathogenic Hypokalemic periodic paralysis 1; Malignant hyperthermia, susceptibility to, 5 2020-06-22 criteria provided, single submitter clinical testing 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.
GeneDx RCV000782249 SCV001779251 likely pathogenic not provided 2021-05-21 criteria provided, single submitter clinical testing Reported in a patient with hypokalemic periodic paralysis (Al-Ghamdi et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may damage or destroy the splice donor site and impact gene splicing; in the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28325641, 26247046, 28012042)
Gharavi Laboratory,Columbia University RCV000782249 SCV000920739 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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