ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs201627041
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001377927 SCV001575382 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-07-26 criteria provided, single submitter clinical testing 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. Variants that disrupt 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 633684). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 26247046, 28012042). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs201627041, gnomAD 0.0009%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1265 of the CACNA1S protein (p.Gln1265His). This variant also falls at the last nucleotide of exon 30, which is part of the consensus splice site for this exon.
GeneDx RCV000782249 SCV001779251 likely pathogenic not provided 2024-09-17 criteria provided, single submitter clinical testing Identified as heterozygous in a patient with hypokalemic periodic paralysis (PMID: 28325641); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site but the effect on protein function is unclear; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28012042, 37510268, 28325641, 26247046, 30476936)
Fulgent Genetics, Fulgent Genetics RCV002493431 SCV002794647 likely pathogenic Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1 2021-11-02 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453618 SCV004177620 likely pathogenic Malignant hyperthermia, susceptibility to, 5 2023-04-11 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003453617 SCV004177621 likely pathogenic Hypokalemic periodic paralysis, type 1 2023-04-11 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003453618 SCV004821415 uncertain significance Malignant hyperthermia, susceptibility to, 5 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 1265 of the CACNA1S protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotypes (ClinVar Variation ID: 633684; PMID: 26247046, 28012042, 28325641). This variant has been identified in 1/251406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
Gharavi Laboratory, Columbia University RCV000782249 SCV000920739 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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