Submissions for variant NM_000719.7(CACNA1C):c.2813T>C (p.Ile938Thr)

gnomAD frequency: 0.00003  dbSNP: rs377165829

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486236	SCV000565758	uncertain significance	not provided	2016-06-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TMEM43 gene. Haywood et al. (2013) observed theE124K variant in two unrelated individuals with ARVC who had a family history of ARVC/DCM, however, theyalso observed this variant in a homozygous state in a control individual. Segregation analysis of E124K with diseasein these families was not completed (Haywood et al., 2013). The E124K variant was also reported in a 47-year-oldfemale with minimal symptoms and no family history of ARVC, who also harbored a DSP variant of uncertainsignificance (Baskin et al., 2013). The NHLBI Exome Sequencing Project and the 1000 Genomes Project reportE124K was observed in 13/8600 (0.2%) alleles from individuals of European background and in 3/694 (0.4%) allelesfrom individuals of Ad Mixed American background, indicating it may be a rare benign variant in these populations.However, the E124K variant is a non-conservative amino acid substitution, which is likely to impact secondaryprotein structure as these residues differ in polarity, charge, size and/or other properties, and this substitution occurs ata position that is conserved across species. Nonetheless, in silico analysis is inconsistent in its predictions as towhether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.This result cannot be interpreted for diagnosis or used for family member screening at this time.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797310	SCV000936859	uncertain significance	Long QT syndrome	2024-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 938 of the CACNA1C protein (p.Ile938Thr). This variant is present in population databases (rs377165829, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 308140). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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	RCV002436155	SCV002749465	benign	Cardiovascular phenotype	2022-02-14	criteria provided, single submitter	clinical testing	This alteration is classified as 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.