Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000505800 | SCV000235768 | uncertain significance | not provided | 2021-03-04 | criteria provided, single submitter | clinical testing | Initially reported in two deceased infant siblings diagnosed with DCM associated with endocardial fibroelastosis; the variant was also identified in their unaffected mother (Mohapatra et al., 2003); Reported in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar Variant ID# 8780; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In vitro studies demonstrated that the K69R variant abolishes the interaction between MLP and alpha-actinin-2 and also demonstrated differential localization in the cell as compared with wild-type protein (Mohapatra et al., 2003); however, additional studies are needed to validate the functional effect of this variant in vivo; This variant is associated with the following publications: (PMID: 22337857, 14567970, 27896284, 23299917, 28790153) |
Invitae | RCV000196843 | SCV000254784 | uncertain significance | Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M | 2022-07-26 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 69 of the CSRP3 protein (p.Lys69Arg). This variant is present in population databases (rs137852764, gnomAD 0.003%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or dilated cardiomyopathy with endocardial fibroelastosis (PMID: 8994428, 14567970, 28790153). ClinVar contains an entry for this variant (Variation ID: 8780). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change affects CSRP3 function (PMID: 14567970, 18250163, 27353086). 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 | RCV000254537 | SCV000318565 | uncertain significance | Cardiovascular phenotype | 2023-04-27 | criteria provided, single submitter | clinical testing | The p.K69R variant (also known as c.206A>G), located in coding exon 2 of the CSRP3 gene, results from an A to G substitution at nucleotide position 206. The lysine at codon 69 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in a proband with dilated cardiomyopathy and endocardiofibroelastosis; however, it was also present in the phenotypically normal mother. In vitro analysis suggested that the mutant protein had an altered cellular localization and failed to bind α-actinin-2 (Mohapatra B et al. Mol. Genet. Metab.;80:207-15). In addition, this alteration was reported to enhance PKCα phosphorylation in vitro (Lange S et al. Nat Commun, 2016 Jun;7:12120). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV000196843 | SCV002775652 | uncertain significance | Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M | 2021-10-09 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000009325 | SCV000029543 | pathogenic | Dilated cardiomyopathy 1M | 2003-09-01 | no assertion criteria provided | literature only | |
Agnes Ginges Centre for Molecular Cardiology, |
RCV001254753 | SCV001430842 | uncertain significance | Hypertrophic cardiomyopathy | 2019-12-06 | no assertion criteria provided | research | The CSRP3 Lys69Arg variant has been previously reported in 2 unrelated DCM cases (Zimmerman RS, et al., 2010; Mohaptra B, et al., 2003). In the case reported by Mohaptra B, et al. (2003) 2 siblings died (both around 2 years of age) from DCM no family history of disease was reported. The variant is present in the Exome Aggregation Consortium dataset (MAF=0.0000165; http://exac.broadinstitute.org/). We identified the CSRP3 Lys69Arg in a HCM proband with no family history of disease or sudden cardiac death. A second variant (MYBPC3 Ser871fs) classified as "pathogenic" has also been identified in this proband. Computational tool SIFT and and MutationTaster predict this variant to be "deleterious" and "disease causing", however PolyPhen-2 predicts this variant to be "benign". In summary, based on current literature, rarity in general populations, and our limited familial data we classify CSRP3 Lys69Arg as variant of "uncertain significance". |