Submissions for variant NM_032578.4(MYPN):c.3481C>A (p.Leu1161Ile)

gnomAD frequency: 0.00123  dbSNP: rs138313730

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000024512	SCV000236066	benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing	Identified in a patient with HCM in the published literature (Purevjav et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 22286171, 27535533)
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, Mass General Brigham 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	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000247848	SCV000318077	benign	Cardiovascular phenotype	2016-04-25	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
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	Primary 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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, 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	Primary dilated cardiomyopathy; Cardiomyopathy; Heart failure	2019-01-24	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000024512	SCV001159431	benign	not provided	2020-08-11	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000206974	SCV001435224	benign	Dilated cardiomyopathy 1KK		criteria provided, single submitter	research	The heterozygous p.Leu1161Ile variant in MYPN has been identified in an American Indian Alaskan individual with hypertrophic cardiomyopathy (PMID: 22286171). This variant has also been identified in >2% of Latino chromosomes and 5 homozygotes by ExAC (http://gnomad.broadinstitute.org/), and in 3 individuals from the NHLBI GO Exome Sequencing Project (PMID: 23299917). In summary, this variant meets criteria to be classified as benign for hypertrophic cardiomyopathy.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216191	SCV004029750	likely benign	not specified	2023-07-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000024512	SCV004042487	benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	MYPN: BS1, BS2
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).
Clinical Genetics, Academic Medical Center	RCV000216191	SCV001919358	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000024512	SCV001958066	likely benign	not provided		no assertion criteria provided	clinical testing