ClinVar Miner

Submissions for variant NM_003476.5(CSRP3):c.436C>T (p.Arg146Cys)

gnomAD frequency: 0.00004  dbSNP: rs376198883
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000994581 SCV000576803 uncertain significance not provided 2021-08-05 criteria provided, single submitter clinical testing Identified in association with HCM in several unrelated individuals referred for genetic testing at GeneDx and in published literature (Burns et al., 2017); 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; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 426380; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 28790153)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769300 SCV000900678 uncertain significance Cardiomyopathy 2017-01-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001071683 SCV001237000 uncertain significance Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 146 of the CSRP3 protein (p.Arg146Cys). This variant is present in population databases (rs376198883, gnomAD 0.004%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 28790153). ClinVar contains an entry for this variant (Variation ID: 426380). 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.
AiLife Diagnostics, AiLife Diagnostics RCV000994581 SCV002503010 uncertain significance not provided 2021-11-18 criteria provided, single submitter clinical testing
Ambry Genetics RCV002329165 SCV002632281 uncertain significance Cardiovascular phenotype 2024-05-22 criteria provided, single submitter clinical testing The p.R146C variant (also known as c.436C>T), located in coding exon 4 of the CSRP3 gene, results from a C to T substitution at nucleotide position 436. The arginine at codon 146 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10). 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, Fulgent Genetics RCV001071683 SCV002789741 uncertain significance Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M 2021-08-03 criteria provided, single submitter clinical testing
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University RCV003319200 SCV003932413 uncertain significance Hypertrophic cardiomyopathy 2023-06-01 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV003319200 SCV004175259 uncertain significance Hypertrophic cardiomyopathy 2023-06-08 criteria provided, single submitter clinical testing The CSRP3 c.436C>T variant is classified as VUS (PM2, PS4_Supporting, PP3) The CSRP3 c.436C>T variant is a single nucleotide change in exon 5/6 of the CSRP3 gene, which is predicted to change the amino acid arginine at position 146 in the protein, to cysteine. The variant has been reported in 9 probands with a clinical presentation of hypertrophic cardiomyopathy (PMID#28790153/ClinVar) and is rare in population databases (gnomAD allele frequency = 0.0039%; 6 het) (PM2). Computational predictions support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs376198883), is reported as ?disease causing in the HGMD database (CM1712561) and is reported as uncertain significance by other diagnostic laboratories (ClinVar Variation ID: 426380).

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