Submissions for variant NM_001127222.2(CACNA1A):c.574C>T (p.Arg192Trp)

gnomAD frequency: 0.00001  dbSNP: rs1057518779

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803741	SCV000943626	uncertain significance	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2018-11-01	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 373933). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 192 of the CACNA1A protein (p.Arg192Trp). 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
GeneDx	RCV001753849	SCV001985411	pathogenic	not provided	2024-09-27	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported as a single heterozygous variant in a patient in published literature with a neurodevelopmental disorder, but detailed clinical information and familial segregation information were not provided (PMID: 25473036); This variant is associated with the following publications: (PMID: 32116539, 32899500, 25473036)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415249	SCV000492568	likely pathogenic	Cerebellar ataxia; Dysarthria; Intention tremor; Spastic paraparesis; Mild global developmental delay	2016-01-22	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004725204	SCV005336236	uncertain significance	CACNA1A-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The CACNA1A c.574C>T variant is predicted to result in the amino acid substitution p.Arg192Trp. This variant has been reported in an individual with a neurodevelopmental disorder (Table 3, Soden et al. 2014. PubMed ID: 25473036). An alternate substitution of this amino acid residue (p.Arg192Gln) has been reported many times in individuals with familial hemiplegic migraine (see for example Ophoff et al. 1996. PubMed ID: 8898206). This variant has not been reported in the large population database gnomAD, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.