rs121908240
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 15P and 4B. PM1PM5PP2PP3_ModeratePP5_Very_StrongBS2
The NM_001127222.2(CACNA1A):c.1499C>T(p.Thr500Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T500A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001127222.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CACNA1A | NM_001127222.2 | c.1499C>T | p.Thr500Met | missense_variant | 11/47 | ENST00000360228.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CACNA1A | ENST00000360228.11 | c.1499C>T | p.Thr500Met | missense_variant | 11/47 | 1 | NM_001127222.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248946Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135064
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461134Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726740
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2018 | - - |
Uncertain significance, flagged submission | clinical testing | Athena Diagnostics | Aug 13, 2020 | - - |
Hereditary episodic ataxia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 25, 2023 | Variant summary: CACNA1A c.1502C>T (p.Thr501Met) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Ion transport domain (IPR005821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248946 control chromosomes (gnomAD). c.1502C>T has been reported in the literature in multiple individuals affected with familial hemiplegic migraine as well as individuals with episodic ataxia (Mantuano_2010, Carreno_2013, Romozzi_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in a gain of channel function (Carreno_2013). The following publications have been ascertained in the context of this evaluation (PMID: 20129625, 24498617, 34320921, 28566750). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=2) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 501 of the CACNA1A protein (p.Thr501Met). This variant is present in population databases (rs121908240, gnomAD 0.003%). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 20129625, 24498617, 34320921). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68421). 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 CACNA1A protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 24498617). For these reasons, this variant has been classified as Pathogenic. - |
Episodic ataxia type 2 Other:1
not provided, no classification provided | literature only | UniProtKB/Swiss-Prot | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at