Submissions for variant NM_001127222.2(CACNA1A):c.4987C>T (p.Arg1663Ter)

dbSNP: rs1555738369

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627239	SCV000748230	pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	Reported previously using alternate nomenclature Arg1665* in an individual with episodic ataxia and their unaffected mother in published literature (Mantuano et al., 2010); Reported previously using alternate nomenclature Arg1669X in an individual with episodic ataxia and migraines who also harbored a missense variant in the CACNA1A gene and a missense variant in the UBR4 gene (Choi et al., 2017); Published functional studies using alternate nomenclature R1669X suggest that this variant exhibits a dominant negative effect on protein function (Jeng et al., 2006); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 16306128, 20129625, 29062094, 33144682)
Revvity Omics, Revvity	RCV000627239	SCV002018028	pathogenic	not provided	2020-10-02	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV002468594	SCV002764956	pathogenic	Episodic ataxia type 2	2022-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002529808	SCV003443217	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-09-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1664*) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CACNA1A function (PMID: 16306128). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 523785). This variant is also known as c.5005C>T (p.Arg1669*). This premature translational stop signal has been observed in individual(s) with CACNA1A-related conditions (PMID: 29062094).
Ambry Genetics	RCV004601224	SCV005099561	pathogenic	Inborn genetic diseases	2024-03-28	criteria provided, single submitter	clinical testing	The c.4990C>T (p.R1664*) alteration, located in exon 32 (coding exon 32) of the CACNA1A gene, consists of a C to T substitution at nucleotide position 4990. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 1664. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. for episodic ataxia type 2; however, its clinical significance for CACNA1A-related neurologic disorder is uncertain, and, it is unlikely to be causative of CACNA1A-related spinocerebellar ataxia This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in two individuals with personal history of episodic ataxia, one of which also had a family history of episodic ataxia (Mantuano, 2010; Choi, 2017). Alternate nomenclature (p.Arg1665* and p.Arg1669*) has been reported in the literature. Based on the available evidence, this alteration is classified as pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542799	SCV001760435	pathogenic	Spinocerebellar ataxia type 6		no assertion criteria provided	clinical testing