Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2_SupportingPP2PP3_StrongPP5_Very_Strong
The NM_001127222.2(CACNA1A):c.5260G>A(p.Gly1754Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Verdict is Pathogenic. Variant got 16 ACMG points.
GnomAD3 genomesCov.: 31 GnomAD4 exome AF: 0.00000120AC: 1AN: 833104Hom.: 0 AF XY: 0.00000260AC XY: 1AN XY: 384708
Submissions by phenotype
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42
|Pathogenic, criteria provided, single submitter||clinical testing||Invitae||Jun 13, 2022||This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1755 of the CACNA1A protein (p.Gly1755Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with generalized epilepsy with typical absence seizures (PMID: 26795593). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 476264). 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. For these reasons, this variant has been classified as Pathogenic. -|
Inborn genetic diseases
|Likely pathogenic, criteria provided, single submitter||clinical testing||Ambry Genetics||Jun 16, 2015||- -|
|Likely pathogenic, criteria provided, single submitter||clinical testing||GeneDx||Apr 21, 2021||Reported in a patient with a developmental disorder in published literature (Lecoquierre et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26795593, 28330790, 31036916) -|
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