Submissions for variant NM_003476.5(CSRP3):c.136A>C (p.Ser46Arg)

gnomAD frequency: 0.00005  dbSNP: rs137852765

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183335	SCV000197497	uncertain significance	not specified	2018-03-02	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV001703415	SCV000235767	uncertain significance	not provided	2023-08-27	criteria provided, single submitter	clinical testing	Identified in patients with HCM or DCM referred for genetic testing at GeneDx and in published literature (Geier et al., 2008; Pugh et al., 2014; Walsh et al., 2017; Janin et al., 2018; Bourfiss et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 24503780, 16352453, 30012424, 36264615, 31919335, 35626289, 35241752, 34697415, 18505755, 27532257)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549408	SCV000657462	uncertain significance	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 46 of the CSRP3 protein (p.Ser46Arg). This variant is present in population databases (rs137852765, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 18505755, 24503780, 35626289). ClinVar contains an entry for this variant (Variation ID: 8781). 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170939	SCV001333590	uncertain significance	Cardiomyopathy	2020-09-18	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000009326	SCV002556692	uncertain significance	Hypertrophic cardiomyopathy 12	2022-03-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381246	SCV002700316	uncertain significance	Cardiovascular phenotype	2021-02-23	criteria provided, single submitter	clinical testing	The p.S46R variant (also known as c.136A>C), located in coding exon 2 of the CSRP3 gene, results from an A to C substitution at nucleotide position 136. The serine at codon 46 is replaced by arginine, an amino acid with dissimilar properties. In one study, this variant was reported in two probands with hypertrophic cardiomyopathy (HCM), and appeared to segregate with disease in one family (Geier C et al. Hum Mol Genet, 2008 Sep;17:2753-65). This variant has also been detected in an individual with dilated cardiomyopathy (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8), and in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur J Hum Genet, 2013 Sep;21:918-28). 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	RCV000549408	SCV002804976	uncertain significance	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2021-08-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001703415	SCV005197657	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing
OMIM	RCV000009326	SCV000029544	pathogenic	Hypertrophic cardiomyopathy 12	2008-09-15	no assertion criteria provided	literature only