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

dbSNP: rs1568446845

Total submissions: 5

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	2019-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 1751 of the CACNA1A protein (p.Arg1751Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has been observed in individuals with episodic ataxia, and spastic paraplegia and ataxia (PMID: 19864665, 28444220). This variant is not present in population databases (ExAC no frequency).
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	2024-09-10	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; Substitution predicted to be within extracellular loop between S5 and S6 transmembrane segments of fourth homologous repeat domain; This variant is associated with the following publications: (PMID: 28444220, 19864665, 31288946, 37301203)
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