Submissions for variant NM_001127222.2(CACNA1A):c.6400C>T (p.Arg2134Cys)

gnomAD frequency: 0.00006  dbSNP: rs121908235

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000710089	SCV000329178	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	Reported in an individual with episodic ataxia (Mantuano et al., 2004) and an individual with small vessel disease-related stroke (Tan et al., 2019); also reported in an individual with cognitive impairment, behavior disorder, hypophonia and dysarthria (Mariani et al., 2016); 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: 15173248, 34426522, 31719132, 27400454, 35401678, 28252636)
Athena Diagnostics Inc	RCV000710089	SCV000612565	uncertain significance	not provided	2018-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV000653342	SCV000775221	likely benign	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-11-22	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000788079	SCV000927077	uncertain significance	Cerebellar ataxia	2018-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710089	SCV001151695	uncertain significance	not provided	2023-11-01	criteria provided, single submitter	clinical testing	CACNA1A: PP2, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174863	SCV001338254	uncertain significance	not specified	2023-02-07	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.6403C>T (p.Arg2135Cys) results in a non-conservative amino acid change located in the C-terminal tail, upstream of the polyglutamine repeat (Mantuano_2004). The CACNA1A gene has a bicistronic mRNA, with the first cistron encoding the voltage-gated calcium channel subunit alpha1A and the second cistron expressing the C-terminal fragment of the alpha1A subunit (alpha1ACT), which is a transcription factor (that also contains the polyglutamine tract), and coordinates the expression of genes involved in neural and Purkinje cell development (PMID: 23827678); our variant of interest affects both of these encoded proteins. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 (i.e. in 11 carriers) in 150946 control chromosomes (gnomAD v3.1, genomes dataset). The variant, c.6403C>T, has also been reported in the literature in heterozygous individuals affected with Episodic ataxia type 2 (Mantuano_2004), Huntington disease-like phenotype (Mariani_2016), small vessel disease-related lacunar stroke (Tan_2019), and spinocerebellar ataxia (Ghorbani_2022). In addition, the variant was also reported in an exome study in a child with developmental delay and spastic diplegia, however the variant was inherited from an asymptomatic father (Baldridge_2017). These reports do not provide unequivocal conclusions about association of the variant with Episodic ataxia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000710089	SCV001713784	uncertain significance	not provided	2020-02-14	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000059310	SCV002025694	uncertain significance	Episodic ataxia type 2	2020-04-18	criteria provided, single submitter	clinical testing	The heterozygous p.Arg2135Cys (also known as p.Arg2136Cys) missense variant identified in CACNA1A has been reported in a patient with episodic ataxia type 2 [PMID: 15173248], and in another individual with developmental delay and spastic diplegia who inherited the variant from asymptomatic father [PMID: 28252636]. The variant has 0.00005107 allele frequency in the gnomAD database (5 out of 97,896 heterozygous alleles) indicating it is a rare allele in the general population. The affected reside is moderately conserved and in silico tools provide conflicting interpretations about pathogenicity of this variant. Functional studies to evaluate the potential pathogenicy of this variant have not been performed to the best of our knowledge. Based on the available evidence, the p.Arg2135Cys variant in the CACNA1A gene is classified as a variant of uncertain significance.
Ambry Genetics	RCV002362698	SCV002660227	uncertain significance	Inborn genetic diseases	2018-05-31	criteria provided, single submitter	clinical testing	The p.R2135C variant (also known as c.6403C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6403. The arginine at codon 2135 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in two individuals in the literature; one with a clinical diagnosis of episodic ataxia type 2 (EA2) and another with Huntingon Disease symptoms who eventually developed cerebellar signs and dysarthria. Of note, this alteration has been called p.R2136C (c.6681C>T) and p.R2140C (c.6418C>T) in the literature (Mantuano E et al. J. Med. Genet., 2004 Jun;41:e82; Mariani LL et al. JAMA Neurol, 2016 Sep;73:1105-14). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000710089	SCV003830270	uncertain significance	not provided	2021-12-21	criteria provided, single submitter	clinical testing
UniProtKB/Swiss-Prot	RCV000059310	SCV000090871	not provided	Episodic ataxia type 2		no assertion provided	not provided
O&I group, Department of Genetics, University Medical Center of Groningen	RCV001849176	SCV001960847	uncertain significance	Spinocerebellar ataxia type 6	2021-07-22	no assertion criteria provided	research
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319317	SCV004023366	likely pathogenic	Tip-toe gait	2022-01-11	no assertion criteria provided	clinical testing