Submissions for variant NM_000722.4(CACNA2D1):c.1648G>T (p.Asp550Tyr)

gnomAD frequency: 0.00011  dbSNP: rs542692632

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619272	SCV000735392	likely benign	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366765	SCV001563080	uncertain significance	Brugada syndrome	2025-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 550 of the CACNA2D1 protein (p.Asp550Tyr). This variant is present in population databases (rs542692632, gnomAD 0.02%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 20817017). ClinVar contains an entry for this variant (Variation ID: 518526). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CACNA2D1 function (PMID: 25527503). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128250	SCV003804709	likely pathogenic	Ventricular fibrillation; Cardiac arrest; Breast carcinoma; Paroxysmal atrial fibrillation	2023-01-17	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PS3_MOD, PS4_MOD, PP2, PP3
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388838	SCV004100793	likely pathogenic	Brugada syndrome 1	2023-10-26	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PS4_MOD,PP2,PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767439	SCV005380656	uncertain significance	not specified	2024-08-12	criteria provided, single submitter	clinical testing	Variant summary: CACNA2D1 c.1648G>T (p.Asp550Tyr) 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 allele was found at a frequency of 7.6e-05 in 251138 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA2D1 causing Developmental And Epileptic Encephalopathy 110, allowing no conclusion about variant significance. c.1648G>T has been reported in the literature in individuals affected with cardiovascular phenotypes (e.g. Burashnikov_2010, Stroeks_2023, Dyssekilde_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Developmental And Epileptic Encephalopathy 110. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Bourdin_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25527503, 20817017, 35470684, 38426305, 37198425). ClinVar contains an entry for this variant (Variation ID: 518526). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001702693	SCV001931929	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001702693	SCV001959338	likely pathogenic	not provided		no assertion criteria provided	clinical testing