Submissions for variant NM_001127222.2(CACNA1A):c.5419G>A (p.Ala1807Thr)

dbSNP: rs1555736565

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818527	SCV000959146	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1808 of the CACNA1A protein (p.Ala1808Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (PMID: 33278787, 35217970; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 500851). 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%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000593477	SCV001813787	pathogenic	not provided	2024-04-22	criteria provided, single submitter	clinical testing	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: 33278787, 34788679, 35722745, 35217970)
Genetics and Molecular Pathology, SA Pathology	RCV002272299	SCV002556697	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-05-10	criteria provided, single submitter	clinical testing	The CACNA1A c.5419G>A variant is classified as LIKELY PATHOGENIC (PS2, PM2, PP3) The CACNA1A c.5419G>A variant is a single nucleotide change in exon 36/47 of the CACNA1A gene, which is predicted to change the amino acid alanine at position 1807 in the protein to threonine. This variant has been identified as a de novo variant in this patient (PS2). This variant has been reported in dbSNP (rs1555736565) but is absent from population databases (PM2). This variant has been reported as a variant of uncertain significance in ClinVar by another diagnostic laboratory (ClinVar Variation ID: 500851). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002272299	SCV002587059	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-10-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000593477	SCV004701562	likely pathogenic	not provided	2024-02-01	criteria provided, single submitter	clinical testing	CACNA1A: PM2, PS4:Moderate, PM6:Supporting, PP2, PP3
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV002272299	SCV004847195	likely pathogenic	Developmental and epileptic encephalopathy, 42	2023-07-12	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004791617	SCV005407775	pathogenic	Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing	PM2_Supporting+PP3_Strong+PS2_Moderate+PS4_Supporting+PP4+PP2
Eurofins Ntd Llc (ga)	RCV000593477	SCV000706970	uncertain significance	not provided	2017-03-20	flagged submission	clinical testing