1-201077916-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000362061.4(CACNA1S):c.1582C>T(p.Arg528Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528G) has been classified as Pathogenic.
Frequency
Consequence
ENST00000362061.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CACNA1S | NM_000069.3 | c.1582C>T | p.Arg528Cys | missense_variant | 11/44 | ENST00000362061.4 | NP_000060.2 | |
CACNA1S | XM_005245478.4 | c.1582C>T | p.Arg528Cys | missense_variant | 11/43 | XP_005245535.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CACNA1S | ENST00000362061.4 | c.1582C>T | p.Arg528Cys | missense_variant | 11/44 | 1 | NM_000069.3 | ENSP00000355192 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251160Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135802
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461722Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727168
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 23, 2024 | Reported as heterozygous in individuals in the published literature with hypokalemic periodic paralysis, and also in two asymptomatic individuals (PMID: 25430699, 33088529); Not observed at significant frequency in large population cohorts (gnomAD); 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: 33088529, 25430699, 37432431) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 09, 2021 | The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 33088529, 25430699). Other variants resulting in a different missense change at this codon have been reported to be pathogenic, suggesting this arginine residue is critical and its disruption is likely to be disease-causing (PMID: 7847370, 7987325, 11034874, 11808349). Computational tools yielded predictions that this amino acid change may be damaging to the protein. Clinical presentation is noted to be variable and reduced penetrance has been reported for females (PMID: 28972032, 15726306, 18835861, 20301512).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
Hypokalemic periodic paralysis, type 1 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Hypokalemic periodic paralysis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 20, 2019 | The p.Arg528Cys variant in CACNA1S has been reported in one individual with hypokalemic periodic paralysis, and segregated with disease in 3 affected male relatives. Two female relatives who carried the variant were asymptomatic (Yang 2014). Of note, incomplete penetrance of hypokalemic periodic paralysis in female individuals has been previously described (Ke 2013). The p.Arg528Cys variant has been identified in 2/111426 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338778). Computational prediction tools and conservation analysis suggest that the p.Arg528Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a different pathogenic variant at this position (p.Arg528His) has been reported in ClinVar (Variation ID: 17625). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg528Cys variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP1, PP3. - |
Congenital myopathy 18 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jun 02, 2023 | The missense c.1582C>T (p.Arg528Cys) variant in the CACNA1S gene has been observed in individual(s) with hypokalaemic periodic paralysis (Yang, Bo et al.,2014). It has also been observed to segregate with disease in related individuals. Other variant(s) that disrupt this residue have been determined to be pathogenic (Katsuno, M et al., 2001). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency (0.0007%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic. The amino acid Arginine at position 528 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid Arginine in CACNA1S is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathoegenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic. - |
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2020 | This sequence change replaces arginine with cysteine at codon 528 of the CACNA1S protein (p.Arg528Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338778, ExAC 0.003%). This variant has been observed in individual(s) with hypokalaemic periodic paralysis (PMID: 25430699). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg528 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 7987325, 11034874, 11808349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Malignant hyperthermia, susceptibility to, 5 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at