VCV000191759.59 - ClinVar

NM_032578.4(MYPN):c.3833G>A (p.Arg1278Gln)

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.

(12)

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(10); Likely benign(1)

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.3833G>A (p.Arg1278Gln)

Variation ID: 191759 Accession: VCV000191759.59

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q21.3 10: 68210325 (GRCh38) [ NCBI UCSC ] 10: 69970082 (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	Jun 8, 2015	Nov 24, 2024	Jan 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_032578.4:c.3833G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_115967.2:p.Arg1278Gln	missense
NM_001256267.2:c.3833G>A	NP_001243196.1:p.Arg1278Gln	missense
NM_001256268.2:c.2951G>A	NP_001243197.1:p.Arg984Gln	missense
NR_045662.4:n.3370G>A		non-coding transcript variant
NR_045663.4:n.3907G>A		non-coding transcript variant
NC_000010.11:g.68210325G>A
NC_000010.10:g.69970082G>A
NG_032118.1:g.109209G>A
LRG_410:g.109209G>A
LRG_410t1:c.3833G>A	LRG_410p1:p.Arg1278Gln

... more HGVS ... less HGVS

Protein change

R1278Q, R984Q

Other names

Canonical SPDI

NC_000010.11:68210324:G:A

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

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.

0.00020 (A)

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

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00044

Exome Aggregation Consortium (ExAC) 0.00046

The Genome Aggregation Database (gnomAD) 0.00052

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062

Links

ClinGen: CA237475 dbSNP: rs142877365 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	1602	1651

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	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Dec 7, 2023	RCV000172081.31
not specified	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 16, 2017	RCV000216203.14
Dilated cardiomyopathy 1KK	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 22, 2024	RCV000230154.15
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Nov 18, 2020	RCV000251155.4
MYPN-related myopathy	Uncertain significance (1)	criteria provided, single submitter	May 25, 2020	RCV002470788.2
Dilated cardiomyopathy 1KK MYPN-related myopathy	Uncertain significance (1)	criteria provided, single submitter	Aug 4, 2021	RCV002478552.2
MYPN-related disorder	Uncertain significance (1)	no assertion criteria provided	May 29, 2024	RCV004730894.1

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 (Nov 18, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318925.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Publications: PubMed (1) PubMed: 23861362 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Uncertain significance (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Not provided Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000054745.1 First in ClinVar: Jun 08, 2015 Last updated: Jun 08, 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: 1
Uncertain significance (Feb 16, 2017)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000604432.1 First in ClinVar: May 29, 2016 Last updated: May 29, 2016
Uncertain significance (Mar 30, 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: SCV000272188.3 First in ClinVar: May 29, 2016 Last updated: Apr 17, 2019	Comment: The p.Arg1278Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 46/66734 European chromosomes b y the … (more) The p.Arg1278Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 46/66734 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142877365). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Arg1278Gln variant is uncertain. (less) Number of individuals with the variant: 1
Uncertain significance (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1KK Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366450.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP4.
Uncertain significance (Sep 01, 2022)	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: SCV001147947.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: MYPN: PM2, BP4 Number of individuals with the variant: 3
Uncertain significance (May 25, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	MYPN-related myopathy Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002768584.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Comment: A heterozygous missense variant was identified, NM_032578.3(MYPN):c.3833G>A in exon 20 of 20 of the MYPN gene. This substitution is predicted to create a minor amino … (more) A heterozygous missense variant was identified, NM_032578.3(MYPN):c.3833G>A in exon 20 of 20 of the MYPN gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 1278 of the protein, NP_115967.2(MYPN):p.(Arg1278Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.045% (127 heterozygotes, 0 homozygotes). Two alternative residue changes at the same location have been reported in the gnomAD database at a frequency of 0.0008% and 0.0012% respectively. It has been previously reported as a VUS in patients with a cardiovascular phenotype (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS). (less)
Uncertain significance (Aug 04, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy 1KK MYPN-related myopathy Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002782360.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Oct 23, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000583342.7 First in ClinVar: May 29, 2016 Last updated: Nov 25, 2023	Comment: Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing … (more) Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (PMID: 23861362); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362) (less)
Uncertain significance (Jan 22, 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: SCV000291124.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1278 of the MYPN protein (p.Arg1278Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1278 of the MYPN protein (p.Arg1278Gln). This variant is present in population databases (rs142877365, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 191759). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Dec 07, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005411018.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 23861362 Comment: BP4 Number of individuals with the variant: 1
Uncertain significance (May 29, 2024)	no assertion criteria provided Method: clinical testing	MYPN-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005337078.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MYPN c.3833G>A variant is predicted to result in the amino acid substitution p.Arg1278Gln. To our knowledge, this variant has not been reported in the … (more) The MYPN c.3833G>A variant is predicted to result in the amino acid substitution p.Arg1278Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.076% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Comment:

This alteration is classified as likely 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:

The p.Arg1278Gln variant in MYPN has not been previously reported in individuals with cardiomyopathy, but has been identified in 46/66734 European chromosomes b y the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs142877365). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. In summary, the cl inical significance of the p.Arg1278Gln variant is uncertain.

Comment:

A heterozygous missense variant was identified, NM_032578.3(MYPN):c.3833G>A in exon 20 of 20 of the MYPN gene. This substitution is predicted to create a minor amino acid change from arginine to glutamine at position 1278 of the protein, NP_115967.2(MYPN):p.(Arg1278Gln). The arginine at this position has high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.045% (127 heterozygotes, 0 homozygotes). Two alternative residue changes at the same location have been reported in the gnomAD database at a frequency of 0.0008% and 0.0012% respectively. It has been previously reported as a VUS in patients with a cardiovascular phenotype (ClinVar). Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).

Comment:

Reported in one individual from a cohort of individuals not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (PMID: 23861362); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23861362)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1278 of the MYPN protein (p.Arg1278Gln). This variant is present in population databases (rs142877365, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 191759). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Comment:

The MYPN c.3833G>A variant is predicted to result in the amino acid substitution p.Arg1278Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.076% of alleles in individuals of European (non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Interpreting secondary cardiac disease variants in an exome cohort.	Ng D	Circulation. Cardiovascular genetics	2013	PMID: 23861362

Text-mined citations for rs142877365 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_032578.4(MYPN):c.3833G>A (p.Arg1278Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs142877365 ...