Submissions for variant NM_001127222.2(CACNA1A):c.5248C>T (p.Arg1750Trp)

dbSNP: rs1568446845

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001204177	SCV001375372	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1751 of the CACNA1A protein (p.Arg1751Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with episodic ataxia, and spastic paraplegia and ataxia (PMID: 19864665, 28444220). ClinVar contains an entry for this variant (Variation ID: 935554). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics	RCV001289289	SCV001477016	likely pathogenic	not provided	2020-09-03	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Conflicting predictions of the effect on the protein. Located in potentially critical domain of the protein. One de novo case with parental identity confirmed.
GeneDx	RCV001289289	SCV001872649	likely pathogenic	not provided	2025-03-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 28444220, 19864665, 31288946, 37301203, 38587696, 39954114)
CeGaT Center for Human Genetics Tuebingen	RCV001289289	SCV001961779	likely pathogenic	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV002463365	SCV002757841	uncertain significance	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2022-04-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005236682	SCV005885218	pathogenic	Hereditary episodic ataxia	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: CACNA1A c.5251C>T (p.Arg1751Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249240 control chromosomes. c.5251C>T has been reported in the literature in multiple heterozygous individuals affected with Episodic Ataxia (e.g., Bertholon_2009, Coutelier_2017, Hirasawa-Inoue_2019, Gogus_2024). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19864665, 28444220, 38587696, 31288946). ClinVar contains an entry for this variant (Variation ID: 935554). Based on the evidence outlined above, the variant was classified as pathogenic.