Submissions for variant NM_001128840.3(CACNA1D):c.1477T>A (p.Cys493Ser)

gnomAD frequency: 0.00037  dbSNP: rs139380111

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001591359	SCV000711551	uncertain significance	not provided	2022-02-15	criteria provided, single submitter	clinical testing	The p.Trp493Arg variant in CACNA1D has not been previously reported in individuals with hearing loss, but has been identified in 0.2% (46/240954) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is located in the last three bases of the exon, which is part of the 5' splice region. Computational tools do not suggest an impact to splicing. However, this information is not predictive enough to rule out pathogenicity. Additional computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4.
GeneDx	RCV001591359	SCV001817250	likely benign	not provided	2021-06-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001591359	SCV002316115	uncertain significance	not provided	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 493 of the CACNA1D protein (p.Trp493Arg). This variant is present in population databases (rs139380111, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with CACNA1D-related conditions. ClinVar contains an entry for this variant (Variation ID: 504803). 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 disruptive. 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.
PreventionGenetics, part of Exact Sciences	RCV004530736	SCV004721856	likely benign	CACNA1D-related disorder	2022-02-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).