VCV000177653.18 - ClinVar

NM_000256.3(MYBPC3):c.3746G>T (p.Gly1249Val)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic (2); Uncertain significance (5)

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.3746G>T (p.Gly1249Val)

Variation ID: 177653 Accession: VCV000177653.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332140 (GRCh38) [ NCBI UCSC ] 11: 47353691 (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	Mar 8, 2017	Feb 15, 2026	Nov 26, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3746G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Gly1249Val	missense
NC_000011.10:g.47332140C>A
NC_000011.9:g.47353691C>A
NG_007667.1:g.25563G>T
LRG_386:g.25563G>T
LRG_386t1:c.3746G>T	LRG_386p1:p.Gly1249Val

... more HGVS ... less HGVS

Protein change

G1249V

Other names

Canonical SPDI

NC_000011.10:47332139:C: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.

Links

ClinGen: CA014754 dbSNP: rs727504259 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	4727	4749

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	Sep 12, 2016	RCV000154241.8
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Nov 26, 2025	RCV000468343.11
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Aug 27, 2025	RCV000766734.7
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 3, 2024	RCV004984686.1

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 (Jan 17, 2017) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000520818.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019	Comment: show A variant of uncertain significance has been identified in the MYBPC3 gene. The G1249V variant has been published in association with HCM (Berge et al., 2014); however, familial segregation information, in vitro functional studies and additional clinical information were not included. The G1249V variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the G1249V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. (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 (Sep 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000203896.3 First in ClinVar: Jan 31, 2015 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 24111713 Comment: show The p.Gly1249Val variant in MYBPC3 has been reported in 4 individuals with HCM ( Berge 2014, LMM data) and was absent from large population studies. Computationa l prediction tools and conservation analysis suggest that the p.Gly1249Val varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In summary, the clinical significance of the p.Gly1249Va l variant is uncertain. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 2

Uncertain Significance (Aug 15, 2023) 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: SCV004827350.1 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)	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: 1 Zygosity: 1 Single Heterozygote

Likely pathogenic (Aug 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007137888.1 First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026	Publications: PubMed (9) PubMed: 24111713‚ 24793961‚ 25611685‚ 27532257‚ 28679633‚ 28971120‚ 33673806‚ 35653365‚ 37652022 Comment: show PP3, PM1, PM2_supporting, PS4 (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: 1

Likely pathogenic (Jul 25, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000927822.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel	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 (Jul 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV005453716.1 First in ClinVar: Jan 13, 2025 Last updated: Jan 13, 2025	Publications: PubMed (6) PubMed: 24111713‚ 24793961‚ 25611685‚ 27532257‚ 28971120‚ 35653365 Comment: show The p.G1249V variant (also known as c.3746G>T), located in coding exon 33 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3746. The glycine at codon 1249 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Dejgaard LA et al. Data Brief, 2017 Dec;15:30-39; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant 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 (Nov 26, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546474.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 24111713‚ 27532257‚ 33673806‚ 37652022 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1249 of the MYBPC3 protein (p.Gly1249Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 33673806, 37652022). ClinVar contains an entry for this variant (Variation ID: 177653). 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

A variant of uncertain significance has been identified in the MYBPC3 gene. The G1249V variant has been published in association with HCM (Berge et al., 2014); however, familial segregation information, in vitro functional studies and additional clinical information were not included. The G1249V variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the G1249V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.

Comment:

The p.Gly1249Val variant in MYBPC3 has been reported in 4 individuals with HCM ( Berge 2014, LMM data) and was absent from large population studies. Computationa l prediction tools and conservation analysis suggest that the p.Gly1249Val varia nt may impact the protein, though this information is not predictive enough to d etermine pathogenicity. In summary, the clinical significance of the p.Gly1249Va l variant is uncertain.

Comment:

The p.G1249V variant (also known as c.3746G>T), located in coding exon 33 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3746. The glycine at codon 1249 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in individuals with hypertrophic cardiomyopathy (HCM) (Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Dejgaard LA et al. Data Brief, 2017 Dec;15:30-39; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1249 of the MYBPC3 protein (p.Gly1249Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 24111713, 27532257, 33673806, 37652022). ClinVar contains an entry for this variant (Variation ID: 177653). 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.

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
Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients.	Hathaway J	BMC cardiovascular disorders	2021	PMID: 33673806
Data on exercise and cardiac imaging in a patient cohort with hypertrophic cardiomyopathy.	Dejgaard LA	Data in brief	2017	PMID: 28971120
Identification of pathogenic gene mutations in LMNA and MYBPC3 that alter RNA splicing.	Ito K	Proceedings of the National Academy of Sciences of the United States of America	2017	PMID: 28679633
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
Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity.	Alfares AA	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25611685
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Genetics of hypertrophic cardiomyopathy in Norway.	Berge KE	Clinical genetics	2014	PMID: 24111713

Text-mined citations for rs727504259 ...

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