1-201078005-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBS1_Supporting
The NM_000069.3(CACNA1S):c.1493G>A(p.Arg498His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000069.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152214Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000187 AC: 47AN: 251488Hom.: 0 AF XY: 0.000228 AC XY: 31AN XY: 135920
GnomAD4 exome AF: 0.000291 AC: 425AN: 1461836Hom.: 1 Cov.: 35 AF XY: 0.000286 AC XY: 208AN XY: 727218
GnomAD4 genome AF: 0.000171 AC: 26AN: 152332Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13AN XY: 74490
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 02, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CACNA1S: PM2:Supporting - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 07, 2024 | Reported in an individual with exertional heat illness who harbored an additional variant in the CACNA1S gene and was not susceptible to malignant hyperthermia by in vitro contracture test (PMID: 25658027); 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: 37937776, 32054689, 25658027, 24195946, 36796140, 36292632) - |
Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1;C5830283:Congenital myopathy 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 28, 2024 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2023 | The c.1493G>A (p.R498H) alteration is located in exon 11 (coding exon 11) of the CACNA1S gene. This alteration results from a G to A substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 26, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 498 of the CACNA1S protein (p.Arg498His). This variant is present in population databases (rs150590855, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of CACNA1S-related conditions (PMID: 25658027, 32054689). ClinVar contains an entry for this variant (Variation ID: 424926). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1S protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at