ClinVar Miner

Submissions for variant NM_032578.4(MYPN):c.59A>G (p.Tyr20Cys) (rs140148105)

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Total submissions: 17
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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, Partners HealthCare 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 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 Does not segregate with disease in family study (genes with incomplete penetrance);Other data supporting benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000024504 SCV000331381 uncertain significance not provided 2015-11-19 criteria provided, single submitter clinical testing
Invitae RCV000043546 SCV000563297 likely benign Dilated cardiomyopathy 1KK 2020-12-01 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 2021-01-27 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

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