Submissions for variant NM_032578.4(MYPN):c.59A>G (p.Tyr20Cys)

gnomAD frequency: 0.00130  dbSNP: rs140148105

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000024504	SCV000051410	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000024504	SCV000236045	likely benign	not provided	2020-11-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23299917, 23861362, 22286171, 26688388, 27171814, 28082330, 26899768, 26498160, 27896284, 22892539, 29875424, 30847666, 32880476)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183576	SCV000272189	likely benign	not specified	2018-12-18	criteria provided, single submitter	clinical testing	The p.Tyr20Cys variant in MYPN is classified as likely benign because it has bee n identified in 0.15% (200/129122) of European chromosomes by gnomAD (http://gno mad.broadinstitute.org). ACMG/AMP criteria applied: PP3, PS3_P, BS1
Ambry Genetics	RCV000254553	SCV000317483	likely benign	Cardiovascular phenotype	2018-05-07	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.
Eurofins Ntd Llc (ga)	RCV000024504	SCV000331381	uncertain significance	not provided	2015-11-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043546	SCV000563297	likely benign	Dilated cardiomyopathy 1KK	2025-02-02	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000183576	SCV000740630	uncertain significance	not specified	2017-04-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000183576	SCV000885813	uncertain significance	not specified	2019-04-13	criteria provided, single submitter	clinical testing	The p.Tyr20Cys variant (rs140148105) was reported in two patients with either HCM or DCM (Purevjav 2012) and one with DCM who had undergone heart transplant surgery (Cuenca 2016). This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the European Non-Finnish population (identified on 200 out of 129,122 chromosomes) and has been reported to the ClinVar database (Variation ID: 31811). This variant was reported to change expression of human MYPN binding proteins and resulted in hypertrophy of the mouse heart (Purevjav 2012). The tyrosine at position 20 is highly conserved and computational analyses of the effects of the p.Tyr20Cys variant on protein structure and function provide conflicting results (SIFT: tolerated, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Tyr20Cys variant with certainty. References: Cuenca S et al. Genetic basis of familial dilated cardiomyopathy patients undergoing heart transplantation. J Heart Lung Transplant. 2016 May;35(5):625-35. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000157381	SCV000995308	likely benign	Primary dilated cardiomyopathy	2017-08-29	criteria provided, single submitter	clinical testing
Loeys Lab, Universiteit Antwerpen	RCV000157381	SCV001572575	uncertain significance	Primary dilated cardiomyopathy	2021-02-26	criteria provided, single submitter	clinical testing	This sequence change results in a missense variant in the MYPN gene (p.(Tyr20Cys)). This variant is present in population databases with a prevalence of 264/282778 in GnomAD (BS1). The variant affects a highly conserved nucleotide and highly conserved amino acid. This variant has been reported in the literature. It has been identified in several unrelated individuals with DCM or HCM (PMID: 22286171). In a mouse model the variant resulted in the development of HCM, disruption of intercalated discs and disturbed expression of desmin, desmoplakin, connexin 43 and vinculin, leading to abnormal assembly of the terminal Z-disc(PMID: 22286171) (PS3). Prediction programs predict a pathogenic effect (Align GVGD C65, pathogenic; Polyphen-2-HumDiv: probably damaging; Polyphen-2-HumVar: probably damaging; SIFT: deleterious; Mutation Taster: disease causing) (PP3). The variant was identified in 3 unrelated patients. The first had DCM and an additional TMEM c.1073C>T variant (classified as pathogenic, BP5), a second patient presented with DCM and a third patient presented with HCM and carried an additional MYBPC3 variant (c.1227-2A>G, classified as likely pathogenic). No data on segregation are available. In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (the criteria for benign and pathogenic are contradictory: BS1; BP5; PS3; PP3).
Mayo Clinic Laboratories, Mayo Clinic	RCV000024504	SCV001716064	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	BS1, PS3_moderate
Revvity Omics, Revvity	RCV000024504	SCV003810983	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224105	SCV003920263	uncertain significance	Dilated cardiomyopathy 1KK; MYPN-related myopathy	2021-03-30	criteria provided, single submitter	clinical testing	MYPN NM_032578.3 exon 2 p.Tyr20Cys (c.59A>G): This variant has been reported in the literature in two individuals with DCM and in one individual with HCM (Purevjav 2012 PMID 22286171; Cuenca 2016 PMID 26899768). However, this variant is also present in 0.1% (200/129122) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/10-69881254-A-G) and is present in ClinVar, with classifications ranging from likely benign to likely pathogenic (Variation ID:31811). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, an in vivo functional study using transgenic mice supports a deleterious effect of this variant (Purevjav 2012 PMID 22286171). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen	RCV000024504	SCV004033046	uncertain significance	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYPN: PM2:Supporting, PP3
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000183576	SCV005039420	likely benign	not specified	2024-03-31	criteria provided, single submitter	clinical testing
Leiden Muscular Dystrophy (MYPN)	RCV000024504	SCV000045808	not provided	not provided	2012-04-27	no assertion provided	curation
OMIM	RCV000043545	SCV000071258	pathogenic	Familial hypertrophic cardiomyopathy 22	2012-05-01	no assertion criteria provided	literature only
OMIM	RCV000043546	SCV000071259	pathogenic	Dilated cardiomyopathy 1KK	2012-05-01	no assertion criteria provided	literature only
Blueprint Genetics	RCV000157381	SCV000207119	likely benign	Primary dilated cardiomyopathy	2014-10-09	no assertion criteria provided	clinical testing
ClinVar Staff, National Center for Biotechnology Information (NCBI)	RCV000043546	SCV000243996	likely pathogenic	Dilated cardiomyopathy 1KK	2013-06-27	no assertion criteria provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000043546	SCV000536916	uncertain significance	Dilated cardiomyopathy 1KK	2016-04-29	no assertion criteria provided	research