Submissions for variant NM_003476.5(CSRP3):c.10T>C (p.Trp4Arg)

gnomAD frequency: 0.00271  dbSNP: rs45550635

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172743	SCV000051519	benign	Primary dilated cardiomyopathy	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150371	SCV000197501	benign	not specified	2019-04-08	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000150371	SCV000235761	likely benign	not specified	2017-10-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201441	SCV000256191	uncertain significance	Hypertrophic cardiomyopathy 12		criteria provided, single submitter	clinical testing
Invitae	RCV001084134	SCV000259819	benign	Hypertrophic cardiomyopathy 12; Dilated cardiomyopathy 1M	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251021	SCV000318092	likely benign	Cardiovascular phenotype	2018-08-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
CeGaT Center for Human Genetics Tuebingen	RCV000487821	SCV000574874	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	CSRP3: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150371	SCV000698205	likely benign	not specified	2019-02-11	criteria provided, single submitter	clinical testing	Variant summary: The variant, CSRP3 c.10T>C (p.Trp4Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0022 in 280268 control chromosomes, predominantly at a frequency of 0.0042 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 170 fold of the estimated maximal expected allele frequency for a pathogenic variant in CSRP3 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In conflict with the population data, in vitro and in vivo functional studies showed that p.W4R completely disrupted T-cap binding, and a mouse model expressing p.W4R showed age- and gene dosage-dependent hypertrophic cardiomyopathy and heart failure phenotype (Knoll 2002, Knoll 2010). However, no human studies are available to date to confirm an effect in humans. Though this variant has been reported in the literature in several patients with either Hypertrophic- or Dilated Cardiomyopathy, it was also found in several controls, with a negative family history of heart disease (Geier 2008, Newman 2005). Moreover, the variant has been shown not to co-segregate with disease in multiple families (Geier 2008, Mohaptra 2003). Additionally, the variant has been reported to co-occur with multiple pathogenic/potentially pathogenic variants, including MYBPC3 F1113I, MYH7 T1377M, MYH7 I511T, MYBPC3 Q1233X and TNNT2 K210del (Bos 2006, Geier 2008, Mohaptra 2003), and it was noted that there was no correlation between the presence of the W4R variant and the severity / progression of the disease (Geier 2008). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign (1x), likely benign (4x) or VUS (1x). Given the strong population and segregation studies data, this variant is likely not a disease-causing mutation in isolation, but functional studies indicate that it affects function and could act as a phenotypic modifier in cardiomyopathies. Taken together, this variant was classified as likely benign, until additional information is available.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000150371	SCV000740561	likely benign	not specified	2017-05-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770316	SCV000901749	uncertain significance	Cardiomyopathy	2017-09-29	criteria provided, single submitter	clinical testing
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV000999619	SCV001156323	likely benign	Hypertrophic cardiomyopathy; Sudden unexplained death	2018-10-10	criteria provided, single submitter	research	This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000487821	SCV001472664	likely benign	not provided	2019-11-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532315	SCV004737277	likely benign	CSRP3-related disorder	2019-09-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Molecular Genetics, Royal Melbourne Hospital	RCV003993742	SCV004812724	likely benign	Hypertrophic cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing
OMIM	RCV000009321	SCV000029539	uncertain significance	Dilated cardiomyopathy 1M	2008-09-15	no assertion criteria provided	literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000487821	SCV001742365	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000150371	SCV001919433	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000487821	SCV001927722	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000487821	SCV001951688	likely benign	not provided		no assertion criteria provided	clinical testing