Submissions for variant NM_001127222.2(CACNA1A):c.4633C>T (p.Arg1545Ter)

dbSNP: rs121909324

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000622947	SCV000741874	pathogenic	Inborn genetic diseases	2016-10-11	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000009032	SCV000883282	likely pathogenic	Episodic ataxia type 2	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Episodic ataxia 2, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1-Moderate => PP1 upgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/10408533).
Fulgent Genetics, Fulgent Genetics	RCV000763032	SCV000893507	pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2021-09-05	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000009032	SCV001190491	pathogenic	Episodic ataxia type 2	2019-10-25	criteria provided, single submitter	research	ACMG codes: PVS1, PS3, PM2, PP5
GeneDx	RCV002466397	SCV002762252	pathogenic	not provided	2022-12-09	criteria provided, single submitter	clinical testing	Described as R1549X and R1547X using alternate nomenclature, published functional studies demonstrate markedly decreased current densities compared to wild type (Jen et al., 2001; 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10408533, 29062094, 29482223, 16306128, 25525159, 29883219, 11723274)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000009032	SCV002767074	pathogenic	Episodic ataxia type 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with CACNA1A-related disease. Episodic ataxia, type 2 (MIM#108500) is caused by variants with a loss of function mechanism (PMID: 28566750). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Reduced penetrance has been reported for patients with episodic ataxia type 2 (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Two families with episodic ataxia, intellectual disability and/or epilepsy have been reported with intrafamilial variability (PMID: 32910250, PMID: 30142438). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER, ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been previously reported in patients with episodic ataxia type 2 (ClinVar, PMID: 10408533, PMID: 29883219). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Athena Diagnostics	RCV002466397	SCV002770606	pathogenic	not provided	2022-04-08	criteria provided, single submitter	clinical testing	This variant segregates with episodic ataxia in at least one family. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as p.R1549X. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant diminished calcium channel activity (PMID: 11723274, 16306128).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512927	SCV003443180	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-06-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CACNA1A function (PMID: 11723274). 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: 8507). This variant is also known as p.Arg1549*. This premature translational stop signal has been observed in individual(s) with CACNA1A-related conditions (PMID: 29062094, 29883219, 31302675). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1546*) 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).
OMIM	RCV000009032	SCV000029249	pathogenic	Episodic ataxia type 2	1999-07-13	no assertion criteria provided	literature only