ClinVar Miner

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

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Total submissions: 15
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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 RCV000183576 SCV000236045 uncertain significance not specified 2017-10-13 criteria provided, single submitter clinical testing The Y20C variant of uncertain significance in the MYPN gene has been reported previously in one individual with HCM and in one individual with DCM; however, no informative segregation data was available (Purevjav et al., 2012). This study also demonstrated both in vivo and in vitro alteration of protein-protein interactions with introduction of the Y20C variant. Of note, transgenic mice expressing MYPN-Y20C developed concentric hypertrophy and dilation of both ventricles, whereas control mice did not develop any cardiac abnormalities (Purevjav et al., 2012). These animal models may not accurately reflect the impact of this variant in a heterozygous human cell, however. The Y20C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution also occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. While the Y20C variant has also been identified in several individuals referred for cardiology genetic testing at GeneDx, thus far, most individuals were also found to harbor additional cardiogenetic variants, and Y20C did not segregate with disease in one family. Furthermore, the Y20C variant was observed in 0.12% of alleles in individuals of European ancestry from the NHLBI Exome Sequencing Project and in 0.14% of alleles in individuals of Non-Finnish European ancestry from the Exome Aggregation Consortium (ExAC), indicating it may be a rare benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
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 2019-12-31 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 RCV000852605 SCV000995308 likely benign Dilated cardiomyopathy 2017-08-29 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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