Submissions for variant NM_032578.4(MYPN):c.2863C>T (p.Arg955Trp)

dbSNP: rs149887823

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172574	SCV000054742	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000172574	SCV000236059	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Reported in association with reduced left-ventricular function, sudden cardiac death and left ventricular non-compaction (Meyer et al., 2013; Seidelmann et al., 2017; Miszalski-Jamka et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar (ClinVar Variant ID# 192126); This variant is associated with the following publications: (PMID: 28087566, 22892539, 23861362, 28798025)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000221588	SCV000272184	uncertain significance	not specified	2015-07-07	criteria provided, single submitter	clinical testing	The p.Arg955Trp variant in MYPN was identified in 1 Caucasian adult with DCM (Me yer 2013). This variant has also been identified in 48/66700 of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs149887823). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg955Trp variant is uncertain.
Ambry Genetics	RCV000619234	SCV000735246	likely benign	Cardiovascular phenotype	2021-05-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000207001	SCV000776947	uncertain significance	Dilated cardiomyopathy 1KK	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 955 of the MYPN protein (p.Arg955Trp). This variant is present in population databases (rs149887823, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of dilated cardiomyopathy, left ventricular noncompaction, or sudden cardiac death (PMID: 22892539, 28087566, 28798025). ClinVar contains an entry for this variant (Variation ID: 192126). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172574	SCV000885812	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing	The MYPN c.2863C>T; p.Arg955Trp variant (rs149887823), is reported in the literature in eight individuals with cardiovascular disease or coronary artery disease risk (Meyer 2013, Miszalski-Jamka 2017, Ng 2013, Seidelmann 2017). This variant is also found in the non-Finnish European population with an allele frequency of 0.073% (94/128,690 alleles) in the Genome Aggregation Database. This variant is reported in ClinVar (Variation ID: 192126). Additionally, another variant at this codon (c.2864G>A, p.R955Q) has been reported in individuals with dilated cardiomyopathy as well as in controls, and the pathogenicity has not yet been yet determined (Mazzarotto 2020, Purevjav 2012). The arginine at codon 955 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.469). Due to limited information, the clinical significance of the p.Arg955Trp variant is uncertain at this time. References: Mazzarotto F et al. Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy. Circulation. 2020 Feb 4;141(5):387-398. Epub 2020 Jan 27. PMID: 31983221. Meyer T et al. Novel mutations in the sarcomeric protein myopalladin in patients with dilated cardiomyopathy. Eur J Hum Genet. 2013 Mar;21(3):294-300. PMID: 22892539. Miszalski-Jamka K et al. Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2017 Aug;10(4):e001763. PMID: 28798025. Ng et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. PMID: 23861362. Purevjav E et al. Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations. Hum Mol Genet. 2012 May 1;21(9):2039-53. doi: 10.1093/hmg/dds022. Epub 2012 Jan 27. PMID: 22286171. Seidelmann SB et al. Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults. Circ Cardiovasc Genet. 2017 Feb;10(1):e001573. PMID: 28087566.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000207001	SCV001368373	uncertain significance	Dilated cardiomyopathy 1KK	2020-01-28	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BS1.
CeGaT Center for Human Genetics Tuebingen	RCV000172574	SCV001748229	uncertain significance	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000172574	SCV003810980	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000207001	SCV004176220	uncertain significance	Dilated cardiomyopathy 1KK	2023-08-03	criteria provided, single submitter	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000207001	SCV000244011	uncertain significance	Dilated cardiomyopathy 1KK	2013-06-27	no assertion criteria provided	literature only