VCV000031791.65 - ClinVar

NM_032578.4(MYPN):c.3335C>T (p.Pro1112Leu)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(23)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(5); Likely benign(6)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_032578.4(MYPN):c.3335C>T (p.Pro1112Leu)

Variation ID: 31791 Accession: VCV000031791.65

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q21.3 10: 68199417 (GRCh38) [ NCBI UCSC ] 10: 69959174 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Dec 22, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032578.4:c.3335C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115967.2:p.Pro1112Leu	missense
NM_001256267.2:c.3335C>T	NP_001243196.1:p.Pro1112Leu	missense
NM_001256268.2:c.2453C>T	NP_001243197.1:p.Pro818Leu	missense
NR_045662.4:n.2872C>T		non-coding transcript variant
NR_045663.4:n.3409C>T		non-coding transcript variant
NC_000010.11:g.68199417C>T
NC_000010.10:g.69959174C>T
NG_032118.1:g.98301C>T
LRG_410:g.98301C>T
LRG_410t1:c.3335C>T	LRG_410p1:p.Pro1112Leu
	Q86TC9:p.Pro1112Leu

... more HGVS ... less HGVS

Protein change

P1112L, P818L

Other names

p.P1112L:CCT>CTT

Canonical SPDI

NC_000010.11:68199416:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

unknown functional consequence

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00260 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00318

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00208

Trans-Omics for Precision Medicine (TOPMed) 0.00213

1000 Genomes Project 0.00260

1000 Genomes Project 30x 0.00297

Exome Aggregation Consortium (ExAC) 0.00303

Links

ClinGen: CA143763 Leiden Muscular Dystrophy (MYPN): MYPN_00003 UniProtKB: Q86TC9#VAR_069659 OMIM: 608517.0002 dbSNP: rs71534278 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
MYPN		-	-	GRCh38 GRCh37	1603	1652

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000024484.42
Familial hypertrophic cardiomyopathy 22	Pathogenic (1)	no assertion criteria provided	May 1, 2012	RCV000043542.12
Primary dilated cardiomyopathy	Likely benign (2)	criteria provided, single submitter	Jun 24, 2013	RCV000157384.11
Dilated cardiomyopathy 1KK	Benign (4)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000043541.28
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Sep 14, 2017	RCV000250407.12
not specified	Conflicting interpretations of pathogenicity (7)	criteria provided, conflicting classifications	Aug 19, 2023	RCV000183595.29
Cardiomyopathy Hypertrophic cardiomyopathy	Benign (1)	criteria provided, single submitter	May 23, 2018	RCV000852613.9
Hypertrophic cardiomyopathy	Uncertain significance (1)	no assertion criteria provided	-	RCV004765307.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely benign (Jun 15, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332270.4 First in ClinVar: Dec 06, 2016 Last updated: Apr 14, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYPN Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Likely benign (Jun 11, 2015)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000270589.3 First in ClinVar: May 29, 2016 Last updated: Apr 14, 2018	Comment: p.Pro1112Leu in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (93/16504) of … (more) p.Pro1112Leu in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (93/16504) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs71534278). (less) Number of individuals with the variant: 6
Likely benign (Dec 23, 2019)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157761.2 First in ClinVar: Feb 10, 2020 Last updated: Jan 26, 2021
Benign (Sep 14, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318447.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 27884173‚ 27896284 Comment: 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 … (more) 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. (less)
Likely benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Cardiomyopathy, dilated Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000051413.1 First in ClinVar: Jun 04, 2015 Last updated: Jun 04, 2015 Comments (2): The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:23861362 for details. (less) Medical sequencing	Number of individuals with the variant: 4
Benign (Apr 17, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000236064.5 First in ClinVar: Jul 05, 2015 Last updated: Apr 09, 2018	Comment: 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 … (more) 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. (less)
Uncertain significance (Jun 22, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000740641.1 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018
Benign (May 23, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995316.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 3
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Dilated cardiomyopathy 1KK Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001138060.2 First in ClinVar: Jan 13, 2020 Last updated: Aug 25, 2023
Likely benign (Aug 19, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004038580.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dilated cardiomyopathy 1KK Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291120.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Likely benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001147940.28 First in ClinVar: Feb 03, 2020 Last updated: Dec 22, 2024	Comment: MYPN: BS2 Number of individuals with the variant: 10
Likely benign (Jun 25, 2014)	no assertion criteria provided Method: clinical testing	Primary dilated cardiomyopathy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV000207122.1 First in ClinVar: Feb 07, 2015 Last updated: Feb 07, 2015	Publications: PubMed (3) PubMed: 18006477‚ 22286171‚ 20801532 Number of individuals with the variant: 1
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, DILATED, 1KK Affected status: not provided Allele origin: germline	OMIM Accession: SCV000071254.2 First in ClinVar: May 26, 2013 Last updated: Nov 06, 2016	Publications: PubMed (2) PubMed: 18006477‚ 22286171 Comment on evidence: In a 38-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a C-T transition in exon 17 of the MYPN … (more) In a 38-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a C-T transition in exon 17 of the MYPN gene, resulting in a pro1112-to-leu (P1112L) substitution at a highly conserved residue in an Ig-1 encoding domain. The mutation was not found in 400 ethnically matched controls. The New York Heart Association (NYHA) class II patient had a left ventricular end-diastolic diameter of 62 mm with an 11-mm interventricular septum and an ejection fraction of 38%; electrocardiogram showed incomplete left bundle branch block as well as nonsustained ventricular tachycardia. Immunofluorescence analysis of transfected rat neonate cardiomyocytes showed sarcomeric apparatus disorganization with the mutant compared to wildtype. In a 64-year-old woman with hypertrophic cardiomyopathy (CMH22; see 615248), Purevjav et al. (2012) identified heterozygosity for a c.3481C-A transition in what they designated as exon 15 of the MYPN gene, resulting in the P1112L substitution at an evolutionarily conserved residue in the alpha-actinin (see 102575)-binding domain. The NYHA class I patient, who had no family history of cardiomyopathy, had interventricular septal and posterior wall thicknesses of 15 mm each, with an ejection fraction of 80%. (less)
Pathogenic (May 01, 2012)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 22 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000071255.2 First in ClinVar: May 26, 2013 Last updated: Nov 06, 2016	Publications: PubMed (2) PubMed: 18006477‚ 22286171 Comment on evidence: In a 38-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a C-T transition in exon 17 of the MYPN … (more) In a 38-year-old man with dilated cardiomyopathy (CMD1KK; 615248), Duboscq-Bidot et al. (2008) identified heterozygosity for a C-T transition in exon 17 of the MYPN gene, resulting in a pro1112-to-leu (P1112L) substitution at a highly conserved residue in an Ig-1 encoding domain. The mutation was not found in 400 ethnically matched controls. The New York Heart Association (NYHA) class II patient had a left ventricular end-diastolic diameter of 62 mm with an 11-mm interventricular septum and an ejection fraction of 38%; electrocardiogram showed incomplete left bundle branch block as well as nonsustained ventricular tachycardia. Immunofluorescence analysis of transfected rat neonate cardiomyocytes showed sarcomeric apparatus disorganization with the mutant compared to wildtype. In a 64-year-old woman with hypertrophic cardiomyopathy (CMH22; see 615248), Purevjav et al. (2012) identified heterozygosity for a c.3481C-A transition in what they designated as exon 15 of the MYPN gene, resulting in the P1112L substitution at an evolutionarily conserved residue in the alpha-actinin (see 102575)-binding domain. The NYHA class I patient, who had no family history of cardiomyopathy, had interventricular septal and posterior wall thicknesses of 15 mm each, with an ejection fraction of 80%. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971570.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Likely pathogenic (Jun 27, 2013)	no assertion criteria provided Method: literature only	Dilated cardiomyopathy 1KK Affected status: yes Allele origin: germline	ClinVar Staff, National Center for Biotechnology Information (NCBI) Accession: SCV000244007.1 First in ClinVar: Feb 02, 2016 Last updated: Feb 02, 2016	Publications: PubMed (1) PubMed: 22286171 Other databases http://web.expasy.org/variant_pa… http://web.expasy.org/variant_pages/VAR_069659.html
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001742222.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917705.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001928193.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001953648.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Uncertain significance (-)	no assertion criteria provided Method: research	hypertrophic cardiomyopathy Affected status: yes Allele origin: unknown	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics Accession: SCV005374728.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024
not provided (Apr 27, 2012)	no classification provided Method: curation	not specified Affected status: not provided Allele origin: germline	Leiden Muscular Dystrophy (MYPN) Accession: SCV000045788.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
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Comment:

p.Pro1112Leu in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (93/16504) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs71534278).

Comment:

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.

Comment:

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.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
unknown functional consequence			Leiden Muscular Dystrophy (MYPN) Accession: SCV000045788.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy.	Nouhravesh N	Molecular genetics & genomic medicine	2016	PMID: 27896284
Revisiting the morbid genome of Mendelian disorders.	Abouelhoda M	Genome biology	2016	PMID: 27884173
Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.	Purevjav E	Human molecular genetics	2012	PMID: 22286171
Analysis of the Z-disc genes PDLIM3 and MYPN in patients with hypertrophic cardiomyopathy.	Bagnall RD	International journal of cardiology	2010	PMID: 20801532
Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.	Duboscq-Bidot L	Cardiovascular research	2008	PMID: 18006477
http://web.expasy.org/variant_pages/VAR_069659.html	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYPN	-	-	-	-

Text-mined citations for rs71534278 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_032578.4(MYPN):c.3335C>T (p.Pro1112Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs71534278 ...