VCV000036610.39 - ClinVar

NM_000256.3(MYBPC3):c.2992C>G (p.Gln998Glu)

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.

(22)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.2992C>G (p.Gln998Glu)

Variation ID: 36610 Accession: VCV000036610.39

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47333924 (GRCh38) [ NCBI UCSC ] 11: 47355475 (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	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2992C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gln998Glu	missense
NC_000011.10:g.47333924G>C
NC_000011.9:g.47355475G>C
NG_007667.1:g.23779C>G
LRG_386:g.23779C>G
LRG_386t1:c.2992C>G	LRG_386p1:p.Gln998Glu
	Q14896:p.Gln998Glu

... more HGVS ... less HGVS

Protein change

Q998E

Other names

Canonical SPDI

NC_000011.10:47333923:G:C

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.

0.00619 (C)

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

The Genome Aggregation Database (gnomAD) 0.00247

Trans-Omics for Precision Medicine (TOPMed) 0.00511

Exome Aggregation Consortium (ExAC) 0.00524

1000 Genomes Project 0.00619

1000 Genomes Project 30x 0.00625

The Genome Aggregation Database (gnomAD), exomes 0.00708

Links

ClinGen: CA013257 UniProtKB: Q14896#VAR_020574 dbSNP: rs11570112 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.
MYBPC3		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3971	3990

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.
Primary dilated cardiomyopathy	Benign (1)	no assertion criteria provided	May 27, 2015	RCV000030288.9
not specified	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 10, 2017	RCV000035545.30
Hypertrophic cardiomyopathy	Benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV000205320.21
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Sep 29, 2015	RCV000250594.11
Primary familial hypertrophic cardiomyopathy	Benign (1)	criteria provided, single submitter	Jun 24, 2013	RCV000172828.10
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Sep 1, 2021	RCV000712370.21
Hypertrophic cardiomyopathy 4	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000625021.15
Left ventricular noncompaction 10	Likely benign (1)	criteria provided, single submitter	Jan 29, 2018	RCV000393234.13
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Mar 9, 2018	RCV000771144.10
Cardiomyopathy Primary dilated cardiomyopathy	Benign (1)	criteria provided, single submitter	Jun 11, 2019	RCV000852650.9
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Benign (1)	criteria provided, single submitter	Apr 1, 2022	RCV002482920.8
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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 (-)	criteria provided, single submitter (LGCM Criteria August 2015) Method: clinical testing	Not specified Affected status: yes Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe) Accession: SCV000256168.1 First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015	Publications: PubMed (3) PubMed: 18929575‚ 15519027‚ 16181148 Number of individuals with the variant: 2
Benign (Sep 01, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001159078.3 First in ClinVar: Feb 10, 2020 Last updated: Jan 08, 2022
Benign (Jun 06, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000842845.1 First in ClinVar: Oct 20, 2018 Last updated: Oct 20, 2018	Publications: PubMed (12) PubMed: 15519027‚ 27650965‚ 22763267‚ 26332594‚ 28498465‚ 25086479‚ 24111713‚ 28971120‚ 24510615‚ 18929575‚ 27600940‚ 23197398
Benign (Nov 30, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000700571.2 First in ClinVar: Jun 01, 2016 Last updated: Nov 08, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3 Number of individuals with the variant: 2 Sex: mixed
Likely benign (Jan 29, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Left ventricular noncompaction 10 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372299.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Likely benign (Jan 29, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000372298.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Publications: PubMed (5) PubMed: 15519027‚ 18929575‚ 16181148‚ 19150014‚ 21839045 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Dec 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170439.12 First in ClinVar: Jun 23, 2014 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 28498465, 22763267, 15519027, 27650965, 26332594, 31918855)
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005224317.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Jun 24, 2013)	criteria provided, single submitter (Ng et al. (Circ Cardiovasc Genet. 2013)) Method: research	Cardiomyopathy, hypertrophic Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000054763.1 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: 3
Likely benign (Oct 14, 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: SCV000740360.1 First in ClinVar: Apr 14, 2018 Last updated: Apr 14, 2018
Benign (May 19, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743543.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Benign (May 31, 2017)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000744831.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Benign (Mar 09, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000902954.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (Jul 10, 2017)	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: SCV000059195.5 First in ClinVar: May 03, 2013 Last updated: Apr 09, 2018	Publications: PubMed (3) PubMed: 16181148‚ 18929575‚ 15519027 Comment: p.Gln998Glu in exon 28 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 9% (90/1000) of Latino … (more) p.Gln998Glu in exon 28 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 9% (90/1000) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs11570112). (less) Number of individuals with the variant: 28
Benign (Jun 11, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dilated cardiomyopathy Cardiomyopathy Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995355.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 5
Benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138291.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Benign (Apr 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002797351.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259242.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Benign (Sep 29, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318155.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	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)
Benign (May 27, 2015)	no assertion criteria provided Method: clinical testing	Primary dilated cardiomyopathy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052955.2 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013
Likely benign (Mar 16, 2016)	no assertion criteria provided Method: provider interpretation	not provided Affected status: unknown Allele origin: germline	Stanford Center for Inherited Cardiovascular Disease, Stanford University Accession: SCV000280254.2 First in ClinVar: Jun 01, 2016 Last updated: Nov 08, 2018	Comment: reclassified to likely benign based on 2015 re-review. Data from that re-review is summarized in DOI: 10.1161/CIRCGENETICS.116.001700.
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: SCV001923416.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

p.Gln998Glu in exon 28 of MYBPC3: This variant is not expected to have clinical significance because it has been identified in 9% (90/1000) of Latino chromosome s by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbS NP rs11570112).

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.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy.	Dejgaard LA	Data in brief	2017	PMID: 28971120
Identification of a novel hypertrophic cardiomyopathy-associated mutation using targeted next-generation sequencing.	Zhao Y	International journal of molecular medicine	2017	PMID: 28498465
Genetic investigation of 100 heart genes in sudden unexplained death victims in a forensic setting.	Christiansen SL	European journal of human genetics : EJHG	2016	PMID: 27650965
Targeted next-generation sequencing helps to decipher the genetic and phenotypic heterogeneity of hypertrophic cardiomyopathy.	Cecconi M	International journal of molecular medicine	2016	PMID: 27600940
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
Detection of mutations in symptomatic patients with hypertrophic cardiomyopathy in Taiwan.	Chiou KR	Journal of cardiology	2015	PMID: 25086479
Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.	Kapplinger JD	Journal of cardiovascular translational research	2014	PMID: 24510615
Genetics of hypertrophic cardiomyopathy in Norway.	Berge KE	Clinical genetics	2014	PMID: 24111713
Impact of systolic dysfunction in genotyped hypertrophic cardiomyopathy.	Fujino N	Clinical cardiology	2013	PMID: 23197398
Population-based variation in cardiomyopathy genes.	Golbus JR	Circulation. Cardiovascular genetics	2012	PMID: 22763267
Double or compound sarcomere mutations in hypertrophic cardiomyopathy: a potential link to sudden death in the absence of conventional risk factors.	Maron BJ	Heart rhythm	2012	PMID: 21839045
[Mutations in sarcomeric genes MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 in patients with hypertrophic cardiomyopathy].	García-Castro M	Revista espanola de cardiologia	2009	PMID: 19150014
Ubiquitin-proteasome system impairment caused by a missense cardiac myosin-binding protein C mutation and associated with cardiac dysfunction in hypertrophic cardiomyopathy.	Bahrudin U	Journal of molecular biology	2008	PMID: 18929575
A novel mutation in the cardiac myosin-binding protein C gene is responsible for hypertrophic cardiomyopathy with severe ventricular hypertrophy and sudden death.	Konno T	Clinical science (London, England : 1979)	2006	PMID: 16181148
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15519027
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYBPC3	-	-	-	-
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Text-mined citations for rs11570112 ...

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_000256.3(MYBPC3):c.2992C>G (p.Gln998Glu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11570112 ...