Submissions for variant NM_001127222.2(CACNA1A):c.3829C>T (p.Arg1277Ter)

dbSNP: rs121909323

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851752	SCV002190549	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-02-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1278*) 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). This premature translational stop signal has been observed in individual(s) with CACNA1A-related conditions (PMID: 9600739, 25735478, 25784583). In at least one individual the variant was observed to be de novo. This variant is also known as c.4110C>T (p.Arg1279*). ClinVar contains an entry for this variant (Variation ID: 8506). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV004700208	SCV005201904	pathogenic	not provided	2023-12-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as variant leads to markedly decreased current densities compared to wild type (PMID: 11723274); 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: 25525159, 11742003, 16306128, 28167673, 11723274, 32899500, 9600739, 25735478, 27667184, 25784583)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786248	SCV005398262	pathogenic	CACNA1A-related complex neurodevelopmental disorder	2024-10-08	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. Type 2 episodic ataxia (MIM#108500) is mostly associated with loss of function, while familial hemiplegic migraine 1, with or without progressive cerebellar ataxia (MIM#141500) is associated with gain of function. Developmental and epileptic encephalopathy 42 (MIM#617106) is associated with both mechanisms, and spinocerebellar ataxia 6 (MIM#183086) is associated with CAG repeat expansion (OMIM, PMID: 25735478, 28566750, 31468518, 32116539). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic family members have been reported to carry the same variant as affected family members (PMID: 10408533, 30142438). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported for episodic ataxia, intellectual disability and/or epilepsy (PMID: 30142438, 32910250). (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 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has been observed in two unrelated families with CACNA1A-related symptoms. (PMID: 25735478, 25784583). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000009031	SCV000029248	pathogenic	Episodic ataxia type 2	2001-11-27	no assertion criteria provided	literature only
E. Rossignol Lab, CHU Ste-Justine, Universite de Montreal	RCV000009031	SCV000196749	pathogenic	Episodic ataxia type 2	2014-11-25	no assertion criteria provided	clinical testing