VCV000042506.48 - ClinVar

NM_000256.3(MYBPC3):c.1144C>T (p.Arg382Trp)

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.

(18)

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.1144C>T (p.Arg382Trp)

Variation ID: 42506 Accession: VCV000042506.48

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47343571 (GRCh38) [ NCBI UCSC ] 11: 47365122 (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 4, 2015	Oct 20, 2024	Feb 5, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.1144C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg382Trp	missense
NC_000011.10:g.47343571G>A
NC_000011.9:g.47365122G>A
NG_007667.1:g.14132C>T
LRG_386:g.14132C>T
LRG_386t1:c.1144C>T	LRG_386p1:p.Arg382Trp
	Q14896:p.Arg382Trp

... more HGVS ... less HGVS

Protein change

R382W

Other names

p.R382W:CGG>TGG

Canonical SPDI

NC_000011.10:47343570: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.

0.01258 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00303

Exome Aggregation Consortium (ExAC) 0.00422

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01028

1000 Genomes Project 0.01258

1000 Genomes Project 30x 0.01280

The Genome Aggregation Database (gnomAD) 0.01409

Trans-Omics for Precision Medicine (TOPMed) 0.01459

Links

ClinGen: CA009811 UniProtKB: Q14896#VAR_020570 dbSNP: rs11570076 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	3960	3979

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 specified	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Jun 24, 2013	RCV000035371.30
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Jul 14, 2015	RCV000243432.11
Hypertrophic cardiomyopathy	Benign (4)	criteria provided, multiple submitters, no conflicts	Feb 5, 2024	RCV000228680.28
Left ventricular noncompaction 10	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000304992.13
Hypertrophic cardiomyopathy 4	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 13, 2018	RCV000625027.14
Cardiomyopathy	Benign (1)	criteria provided, single submitter	Mar 19, 2018	RCV000771760.10
Arrhythmogenic right ventricular dysplasia 1	Likely benign (1)	criteria provided, single submitter	Nov 15, 2019	RCV001256909.10
not provided	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Dec 21, 2022	RCV001811242.17

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.
Benign (Oct 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: SCV000743564.1 First in ClinVar: Apr 20, 2018 Last updated: Apr 20, 2018
Likely benign (Nov 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Arrhythmogenic right ventricular dysplasia 1 Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV001433419.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020
Benign (Mar 19, 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: SCV000904418.1 First in ClinVar: May 20, 2019 Last updated: May 20, 2019
Benign (Jun 09, 2011)	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: SCV000059019.5 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Publications: PubMed (1) PubMed: 15519027 Comment: This variant is classified as benign based on its high frequency in the general population (rs11570076; MAF = 7%). Number of individuals with the variant: 80
Benign (Dec 21, 2022)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001158983.6 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004834669.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 768
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: SCV005224329.1 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	not specified Affected status: unknown Allele origin: unknown	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000054772.1 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: 2
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000303182.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jul 06, 2011)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000170459.11 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	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)
Benign (Jan 13, 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: SCV000372363.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Likely benign (Jan 13, 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: SCV000372362.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 31, 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: SCV000284203.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (Jul 14, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318208.7 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 (-)	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: SCV001952145.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 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: SCV001918766.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Benign (Oct 10, 2022)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Cohesion Phenomics Accession: SCV003800604.2 First in ClinVar: Feb 13, 2023 Last updated: Apr 15, 2023
Benign (-)	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: SCV005374526.1 First in ClinVar: Oct 20, 2024 Last updated: Oct 20, 2024
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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.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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 in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15519027

Text-mined citations for rs11570076 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.1144C>T (p.Arg382Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs11570076 ...