VCV000810763.11 - ClinVar

NM_000256.3(MYBPC3):c.3452C>T (p.Ala1151Val)

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.

(6)

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.

Uncertain significance

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.3452C>T (p.Ala1151Val)

Variation ID: 810763 Accession: VCV000810763.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332852 (GRCh38) [ NCBI UCSC ] 11: 47354403 (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	Feb 7, 2020	May 1, 2024	Dec 28, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3452C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ala1151Val	missense
NC_000011.10:g.47332852G>A
NC_000011.9:g.47354403G>A
NG_007667.1:g.24851C>T
LRG_386:g.24851C>T
LRG_386t1:c.3452C>T	LRG_386p1:p.Ala1151Val

... more HGVS ... less HGVS

Protein change

A1151V

Other names

Canonical SPDI

NC_000011.10:47332851: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.

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

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00008

Links

dbSNP: rs779884363 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.
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Dec 28, 2023	RCV000999604.6
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	May 12, 2023	RCV001184393.4
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 30, 2019	RCV002454250.2
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Sep 30, 2021	RCV002505527.1

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.
Uncertain significance (Oct 15, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute Accession: SCV001156307.1 First in ClinVar: Feb 07, 2020 Last updated: Feb 07, 2020	Publications: PubMed (1) PubMed: 27532257 Comment: MYBPC3 Ala1151Val has been reported in at least 1 HCM proband (Walsh R, et al., 2017) and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). … (more) MYBPC3 Ala1151Val has been reported in at least 1 HCM proband (Walsh R, et al., 2017) and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease who also harbours a second MYBPC3 variant (c.821+1G>C). In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be 'tolerated'. As such we classify this as a variant of 'uncertain significance'. (less)
Uncertain Significance (Dec 07, 2023)	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: SCV004836595.1 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)	Publications: PubMed (4) PubMed: 27532257‚ 31983221‚ 32841044‚ 33782553 Comment: This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553) and in individuals affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 9/235592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less) Number of individuals with the variant: 7
Uncertain significance (May 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001350357.3 First in ClinVar: Jun 22, 2020 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 27532257‚ 31983221‚ 32841044‚ 33782553 Comment: This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553) and in individuals affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 9/235592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Uncertain significance (Sep 30, 2021)	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: SCV002814070.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Dec 28, 2023)	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: SCV003016162.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 27532257‚ 33782553 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1151 of the MYBPC3 protein (p.Ala1151Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1151 of the MYBPC3 protein (p.Ala1151Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257, 33782553). ClinVar contains an entry for this variant (Variation ID: 810763). 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 (May 30, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002617055.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 22958901‚ 27532257 Comment: The p.A1151V variant (also known as c.3452C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide … (more) The p.A1151V variant (also known as c.3452C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3452. The alanine at codon 1151 is replaced by valine, an amino acid with similar properties. This variant has been reported in the Jackson Heart Study cohort and has been reported in a hypertrophic cardiomyopathy clinical genetic testing cohort; however, clinical details were limited in both studies (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

MYBPC3 Ala1151Val has been reported in at least 1 HCM proband (Walsh R, et al., 2017) and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in a HCM proband with no family history of disease who also harbours a second MYBPC3 variant (c.821+1G>C). In silico tools PolyPhen2 and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be 'tolerated'. As such we classify this as a variant of 'uncertain significance'.

Comment:

This missense variant replaces alanine with valine at codon 1151 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 32841044, 33782553) and in individuals affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 9/235592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1151 of the MYBPC3 protein (p.Ala1151Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27532257, 33782553). ClinVar contains an entry for this variant (Variation ID: 810763). 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 p.A1151V variant (also known as c.3452C>T), located in coding exon 31 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3452. The alanine at codon 1151 is replaced by valine, an amino acid with similar properties. This variant has been reported in the Jackson Heart Study cohort and has been reported in a hypertrophic cardiomyopathy clinical genetic testing cohort; however, clinical details were limited in both studies (Bick AG et al. Am. J. Hum. Genet., 2012 Sep;91:513-9; Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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
Computational prediction of protein subdomain stability in MYBPC3 enables clinical risk stratification in hypertrophic cardiomyopathy and enhances variant interpretation.	Thompson AD	Genetics in medicine : official journal of the American College of Medical Genetics	2021	PMID: 33782553
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.	Helms AS	Circulation. Genomic and precision medicine	2020	PMID: 32841044
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.	Mazzarotto F	Circulation	2020	PMID: 31983221
Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples.	Walsh R	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 27532257
Burden of rare sarcomere gene variants in the Framingham and Jackson Heart Study cohorts.	Bick AG	American journal of human genetics	2012	PMID: 22958901

Text-mined citations for rs779884363 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.3452C>T (p.Ala1151Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779884363 ...