VCV000164086.23 - ClinVar

NM_000256.3(MYBPC3):c.2249C>T (p.Thr750Met)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic (1); Uncertain significance (6)

7 out of 7 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.2249C>T (p.Thr750Met)

Variation ID: 164086 Accession: VCV000164086.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47338579 (GRCh38) [ NCBI UCSC ] 11: 47360130 (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	May 29, 2016	Feb 15, 2026	Nov 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2249C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Thr750Met	missense
NC_000011.10:g.47338579G>A
NC_000011.9:g.47360130G>A
NG_007667.1:g.19124C>T
LRG_386:g.19124C>T
LRG_386t1:c.2249C>T	LRG_386p1:p.Thr750Met

... more HGVS ... less HGVS

Protein change

T750M

Other names

Canonical SPDI

NC_000011.10:47338578:G:A

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.

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA011943 dbSNP: rs727503189 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	4725	4747

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	Uncertain significance (1)	criteria provided, single submitter	Aug 29, 2019	RCV000151100.6
Hypertrophic cardiomyopathy	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Nov 1, 2025	RCV000628954.14
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 1, 2025	RCV001185780.6
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	May 23, 2024	RCV002426715.3
not provided	Uncertain significance (1)	criteria provided, single submitter	Nov 25, 2022	RCV002460930.1
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Feb 18, 2022	RCV002492557.1

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.	Expand all rows Collapse all rows 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 (Nov 25, 2022) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV002757649.1 First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022	Comment: show In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 34097875, 24111713) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Feb 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002785440.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain Significance (Sep 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	All of Us Research Program, National Institutes of Health Accession: SCV004842369.2 First in ClinVar: Apr 20, 2024 Last updated: Dec 14, 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 (3) PubMed: 22267749‚ 24111713‚ 27532257 Comment: show This missense variant replaces threonine with methionine at codon 750 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 six individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 24111713, 27532257, ClinVar SCV000198863.5) ). This variant has been identified in 8/280596 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 11 Zygosity: 11 Single Heterozygotes

Likely pathogenic (Nov 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000749862.8 First in ClinVar: May 28, 2018 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 24111713‚ 27532257‚ 28492532‚ 37652022 Comment: show This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 750 of the MYBPC3 protein (p.Thr750Met). This variant is present in population databases (rs727503189, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 164086). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Aug 29, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198863.5 First in ClinVar: Feb 02, 2015 Last updated: Jul 03, 2020	Publications: PubMed (2) PubMed: 22267749‚ 24111713 Comment: show The p.Thr750Met variant in MYBPC3 has previously been reported in 5 individuals with HCM (Page 2012, Berge 2014, LMM data). This variant has also been identified in 0.01% (3/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #164086). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4, . (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 2

Uncertain significance (May 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002728821.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (4) PubMed: 24111713‚ 27532257‚ 33432171‚ 35653365 Comment: show The p.T750M variant (also known as c.2249C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2249. The threonine at codon 750 is replaced by methionine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing; however, details were limited (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Jul 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001352071.5 First in ClinVar: Jun 22, 2020 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 22267749‚ 24111713‚ 27532257‚ 37652022 Comment: show This missense variant replaces threonine with methionine at codon 750 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 24111713, 27532257, 37652022ClinVar Variation ID: 164086). This variant has been identified in 8/280596 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Comment:

This missense variant replaces threonine with methionine at codon 750 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 six individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 24111713, 27532257, ClinVar SCV000198863.5) ). This variant has been identified in 8/280596 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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 750 of the MYBPC3 protein (p.Thr750Met). This variant is present in population databases (rs727503189, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 164086). 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 tolerated. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

The p.Thr750Met variant in MYBPC3 has previously been reported in 5 individuals with HCM (Page 2012, Berge 2014, LMM data). This variant has also been identified in 0.01% (3/30602) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org) and reported in ClinVar (Variation ID #164086). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BP4, .

Comment:

The p.T750M variant (also known as c.2249C>T), located in coding exon 23 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2249. The threonine at codon 750 is replaced by methionine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts and cohorts referred for HCM genetic testing; however, details were limited (Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Walsh R et al. Genet Med, 2017 02;19:192-203). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces threonine with methionine at codon 750 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in six individuals affected with hypertrophic cardiomyopathy (PMID: 22267749, 24111713, 27532257, 37652022ClinVar Variation ID: 164086). This variant has been identified in 8/280596 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings.	McGurk KA	American journal of human genetics	2023	PMID: 37652022
Molecular genetics in 4408 cardiomyopathy probands and 3008 relatives in Norway: 17 years of genetic testing in a national laboratory.	Stava TT	European journal of preventive cardiology	2022	PMID: 35653365
Exome-wide evaluation of rare coding variants using electronic health records identifies new gene-phenotype associations.	Park J	Nature medicine	2021	PMID: 33432171
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
Genetics of hypertrophic cardiomyopathy in Norway.	Berge KE	Clinical genetics	2014	PMID: 24111713
Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome.	Page SP	Circulation. Cardiovascular genetics	2012	PMID: 22267749

Text-mined citations for rs727503189 ...

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 Feb 15, 2026