Submissions for variant NM_001127222.2(CACNA1A):c.5155G>A (p.Asp1719Asn)

gnomAD frequency: 0.00010  dbSNP: rs368257155

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413582	SCV000492328	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CACNA1A gene. The D1720N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D1720N variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D1720N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position where amino acids with similar properties to Aspartic acid are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV002318368	SCV000851224	uncertain significance	Inborn genetic diseases	2016-09-07	criteria provided, single submitter	clinical testing	The p.D1720N variant (also known as c.5158G>A), located in coding exon 34 of the CACNA1A gene, results from a G to A substitution at nucleotide position 5158. The aspartic acid at codon 1720 is replaced by asparagine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs368257155. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.02% (2/12526) total alleles studied, having been observed in 0.02% (1/4136) African American alleles and 0.01% (1/8390) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000996784	SCV001151704	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
Invitae	RCV001216305	SCV001388095	likely benign	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-08	criteria provided, single submitter	clinical testing