ClinVar Miner

Submissions for variant NM_032578.3(MYPN):c.3481C>A (p.Leu1161Ile) (rs138313730)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000216191 SCV000236066 benign not specified 2017-03-24 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000206974 SCV000267413 uncertain significance Dilated cardiomyopathy 1KK 2016-03-18 criteria provided, single submitter reference population
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000216191 SCV000269405 benign not specified 2015-06-03 criteria provided, single submitter clinical testing p.Leu1161Ile in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 2.8% (320/11566) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138313730).
Invitae RCV000206974 SCV000291122 benign Dilated cardiomyopathy 1KK 2018-01-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000247848 SCV000318077 benign Cardiovascular phenotype 2016-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000024512 SCV000511278 likely benign not provided 2017-02-07 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624690 SCV000740629 uncertain significance Familial dilated cardiomyopathy 2017-03-28 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000206974 SCV000743691 likely benign Dilated cardiomyopathy 1KK 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000206974 SCV000745068 benign Dilated cardiomyopathy 1KK 2017-05-31 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000852614 SCV000995317 likely benign Cardiomyopathy; Heart failure; Dilated cardiomyopathy 2019-01-24 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (MYPN) RCV000024512 SCV000045816 not provided not provided 2012-04-27 no assertion provided curation
ClinVar Staff, National Center for Biotechnology Information (NCBI) RCV000206974 SCV000244008 uncertain significance Dilated cardiomyopathy 1KK 2013-06-27 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000024512 SCV000280393 benign not provided 2016-10-13 no assertion criteria provided provider interpretation p.Leu1161Ile (c.3481 C>A) in the MYPN gene Given the weak disease-gene association, the weak case data, and the presence in ancestry-matched general population samples, we consider this variant a variant of uncertain significance. MYPN (NM_032578.2) encodes myopalladin, a protein component of the sarcomere. Heterozygous mutations in MYPN have been reported in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) (Purevjav et al. 2012 Hum Molec Genet 21(9):2039-2053; Meyer et al. 2012 Eur J Hum Genet Epub ahead of print). However, when Megan Grove from our team reviewed the supporting data in 2012 we felt that it was weak. The variant has been seen in at least 1 unrelated case of hypertrophic cardiomyopathy (not including this patient's family). There is no segregation data available. Purevjav et al (2012) observed the variant in an American Indian/Alaskan male with HCM who had undergone myectomy. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The variant occurs in the alpha-actinin binding domain. This is a conservative amino acid change from nonpolar leucine to a nonpolar isoleucine at a residue that is highly conserved across vertebrate species (it is a nonpolar phenylalanine in squirrel). It is predicted to be "probably damaging" and "tolerated" by PolyPhen and SIFT in silico analyses, respectively. [UPDATED in 2016] In total the variant has not been seen in at least 400 of >60,000 published controls and individuals from publicly available population datasets. It is present in 400 individuals in ExAC, across multiple ethnicities. The variant was reported in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of September 12th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per GeneDx, the variant was observed in the 1000 Genomes samples: 3/551 (0.5%) alleles from individuals of Asian background and in 1/349 (0.3%) alleles of individuals of Hispanic ancestry. The variant was not observed in the following published control samples: 1020 (Purejeav et al 2012).

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