Submissions for variant NM_032578.4(MYPN):c.3124C>T (p.Arg1042Cys)

gnomAD frequency: 0.00034  dbSNP: rs151282801

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228976	SCV000291118	likely benign	Dilated cardiomyopathy 1KK	2025-01-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000252987	SCV000319023	likely benign	Cardiovascular phenotype	2021-02-09	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.
GeneDx	RCV000421407	SCV000536532	uncertain significance	not provided	2025-03-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in patients with cardiomyopathy in published literature; several patients harbored additional cardiogenetic variants (PMID: 28798025, 26084686, 35284542, 30847666); This variant is associated with the following publications: (PMID: 26084686, 35284542, 30847666, 28798025)
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000228976	SCV000743690	uncertain significance	Dilated cardiomyopathy 1KK	2016-08-22	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000228976	SCV000745064	uncertain significance	Dilated cardiomyopathy 1KK	2017-05-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000421407	SCV001147937	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824644	SCV002074528	likely benign	not specified	2022-01-04	criteria provided, single submitter	clinical testing	Variant summary: MYPN c.3124C>T (p.Arg1042Cys) 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 0.00041 in 251424 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYPN causing Cardiomyopathy phenotype (5e-05), strongly suggesting that the variant is benign. c.3124C>T has been reported in the literature in individuals affected with Cardiomyopathy, including dilated cardiomyopathy, hypertrophic cardiomyopathy and left ventricular hypertrabeculation (Akinrinade_2015, Miszalski-Jamka_2017, van Lint_2019). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. A co-occurrence with a pathogenic variant has been reported (TTNI3 c.407G>A, p.Arg136Gln; van Lint_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign and five as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000421407	SCV005411014	uncertain significance	not provided	2024-04-11	criteria provided, single submitter	clinical testing	BS1
Blueprint Genetics	RCV000143934	SCV000188812	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-10-15	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000228976	SCV000732958	uncertain significance	Dilated cardiomyopathy 1KK		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000421407	SCV001925617	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000421407	SCV001955114	uncertain significance	not provided		no assertion criteria provided	clinical testing