Submissions for variant NM_001127222.2(CACNA1A):c.1361G>A (p.Arg454Gln)

gnomAD frequency: 0.00004  dbSNP: rs561858384

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658823	SCV000535295	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	Reported in an individual with episodic ataxia in published literature (Isaacs et al., 2017).; 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: 32899500, 32116539, 28540055)
Athena Diagnostics	RCV000420690	SCV000612506	uncertain significance	not specified	2016-09-26	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000658823	SCV000701760	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000658823	SCV000780619	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	CACNA1A: PP2, PS4:Supporting
Ambry Genetics	RCV002311506	SCV000846511	uncertain significance	Inborn genetic diseases	2016-05-17	criteria provided, single submitter	clinical testing	The p.R455Q variant (also known as c.1364G>A), located in coding exon 11 of the CACNA1A gene, results from a G to A substitution at nucleotide position 1364. The arginine at codon 455 is replaced by glutamine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6014 samples (12028 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795075	SCV000934516	likely benign	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-12-11	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000420690	SCV002061962	uncertain significance	not specified	2017-08-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000420690	SCV004029253	uncertain significance	not specified	2023-07-21	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.1364G>A (p.Arg455Gln) results in a conservative amino acid change located in the ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 248320 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1364G>A has been reported in the literature in the heterozygous state in an individual with symptoms consistent with Episodic Ataxia (Isaacs_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28540055). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments, classifying the variant as either VUS (n=5), likely pathogenic (n=1), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV003319199	SCV004023233	likely pathogenic	Tip-toe gait	2021-11-08	no assertion criteria provided	clinical testing	Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. Our patients all walk on tiptoe, so they show similar symptoms. When we genetically test them with our toe walking panel, we find that around 90 per cent of them have a genetic variant that explains their toe walking. These can be assigned, for example, to the area of myopathies (such as variants of the COL6A3 gene), the area of hereditary neuropathies (such as variants of the KMT2C gene) or the area of metabolic diseases (such as variants of the PYGM gene). In a smaller group of patients with almost identical symptoms, no abnormality is found in the genes of our panel, but spastic paraplegia can be detected. In another small group of our toe walkers, no abnormalities can be detected in the genes analysed in our toe walking panel, nor do they suffer from spastic paraplegia, as is also the case with healthy children. In contrast to these, however, they show a tiptoe gait. These patients suffer from infantile cerebral palsy, in which toe walking can also be observed.