Submissions for variant NM_000722.4(CACNA2D1):c.435A>G (p.Ile145Met)

gnomAD frequency: 0.00001  dbSNP: rs756765026

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000638716	SCV000760258	uncertain significance	Brugada syndrome	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 145 of the CACNA2D1 protein (p.Ile145Met). This variant is present in population databases (rs756765026, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA2D1-related conditions. ClinVar contains an entry for this variant (Variation ID: 532105). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Ambry Genetics	RCV002331150	SCV002627948	uncertain significance	Cardiovascular phenotype	2020-08-27	criteria provided, single submitter	clinical testing	The p.I145M variant (also known as c.435A>G), located in coding exon 6 of the CACNA2D1 gene, results from an A to G substitution at nucleotide position 435. The isoleucine at codon 145 is replaced by methionine, an amino acid with highly similar properties. This variant was detected in one individual from an arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003420117	SCV004106442	uncertain significance	CACNA2D1-related disorder	2022-11-06	criteria provided, single submitter	clinical testing	The CACNA2D1 c.435A>G variant is predicted to result in the amino acid substitution p.Ile145Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0097% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-81746451-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
CeGaT Center for Human Genetics Tuebingen	RCV003432676	SCV004162363	uncertain significance	not provided	2022-06-01	criteria provided, single submitter	clinical testing	CACNA2D1: PP2, BP4