Submissions for variant NM_001127222.2(CACNA1A):c.4927G>A (p.Asp1643Asn)

dbSNP: rs1064795531

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480159	SCV000571438	pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	Identified heterozygous in an individual with hypoplasia of the cerebellum and global developmental delay (PMID: 36028527); 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: 34758253, 37555011, 34445196, 36028527)
CeGaT Center for Human Genetics Tuebingen	RCV000480159	SCV001501249	uncertain significance	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV001643203	SCV001519110	pathogenic	Episodic ataxia type 2	2021-01-04	criteria provided, single submitter	research
Invitae	RCV001856860	SCV002273836	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-05-20	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 422063). For these reasons, this variant has been classified as Pathogenic. 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. This missense change has been observed in individual(s) with clinical features of CACNA1A-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1644 of the CACNA1A protein (p.Asp1644Asn).
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227168	SCV002506555	likely pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 52	2022-03-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001264726	SCV002767527	likely pathogenic	Developmental and epileptic encephalopathy, 42	2020-05-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v0.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: 0103 - Both loss and gain of function are known mechanism of disease for this gene. 0107 - This gene is known to be associated with autosomal dominant disease. 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine (exon 31). 0301 - Variant is absent from gnomAD. 0501 - Missense variant consistently predicted to be damaging by in silico tools or highly conserved with a major amino acid change. 0600 - Variant is located in an annotated domain or motif that does not have a well established function (extracellular region of Ion-trans domain; PDB, NCBI, DECIPHER). 0603 - Missense variant in a region that is highly intolerant to missense variation (constraint). 0705 - No comparable variants in relevant codon/region have previous evidence for pathogenicity. 0807 - Variant has not previously been reported in a clinical context (1X VUS in ClinVar). 0905 - No published segregation evidence has been identified for this variant. 1007 - No published functional evidence has been identified for this variant. 1204 - De novo variant (parental status not tested but assumed) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Pediatric Department, Xiangya Hospital, Central South University	RCV001643203	SCV003930356	likely pathogenic	Episodic ataxia type 2	2021-01-07	criteria provided, single submitter	clinical testing
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264726	SCV001442957	likely pathogenic	Developmental and epileptic encephalopathy, 42	2020-04-03	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001542801	SCV001760437	likely pathogenic	Spinocerebellar ataxia type 6		no assertion criteria provided	clinical testing