VCV000042618.25 - ClinVar

NM_000256.3(MYBPC3):c.2320G>A (p.Ala774Thr)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance
Uncertain significance (9)

9 out of 11 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.2320G>A (p.Ala774Thr)

Variation ID: 42618 Accession: VCV000042618.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337783 (GRCh38) [ NCBI UCSC ] 11: 47359334 (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	Dec 6, 2014	Feb 15, 2026	Dec 11, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2320G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Ala774Thr	missense
NC_000011.10:g.47337783C>T
NC_000011.9:g.47359334C>T
NG_007667.1:g.19920G>A
LRG_386:g.19920G>A
LRG_386t1:c.2320G>A	LRG_386p1:p.Ala774Thr

... more HGVS ... less HGVS

Protein change

A774T

Other names

Canonical SPDI

NC_000011.10:47337782:C:T

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) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA012113 dbSNP: rs368104687 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.
Primary familial hypertrophic cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jun 1, 2014	RCV000148678.3
Hypertrophic cardiomyopathy 4	Uncertain significance (1)	no assertion criteria provided	Aug 13, 2015	RCV000415709.1
Left ventricular noncompaction 10	Uncertain significance (1)	no assertion criteria provided	Aug 13, 2015	RCV000415662.1
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 11, 2025	RCV000770335.8
not provided	Uncertain significance (1)	criteria provided, single submitter	Jun 27, 2025	RCV000766349.3
Hypertrophic cardiomyopathy	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jun 11, 2024	RCV001071057.9
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Sep 22, 2021	RCV002504874.1
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Aug 31, 2021	RCV004018748.1

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 (Jun 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Study: Canadian Open Genetics Repository Accession: SCV000901769.1 First in ClinVar: May 06, 2019 Last updated: May 06, 2019	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 (Jun 27, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208087.12 First in ClinVar: Jan 31, 2015 Last updated: Jul 13, 2025	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; Reported in association with HCM in published literature (PMID: 21839045, 27532257, 33302605); This variant is associated with the following publications: (PMID: 27532257, 23299917, 25637381, 34426522, 37652022, 33302605, 21839045) (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 (Jan 17, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001236339.4 First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 21839045‚ 27532257‚ 33302605 Comment: show This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 774 of the MYBPC3 protein (p.Ala774Thr). This variant is present in population databases (rs368104687, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 21839045, 27532257, 33302605). ClinVar contains an entry for this variant (Variation ID: 42618). 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 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

Uncertain Significance (Jun 11, 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: SCV004842363.2 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 (4) PubMed: 21839045‚ 27532257‚ 31983221‚ 33302605 Comment: show This missense variant replaces alanine with threonine at codon 774 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy, including two related individuals who were diagnosed in the neonatal period (PMID: 21839045, 27532257, 33302605). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 2/152072 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: 16 Zygosity: 16 Single Heterozygotes

Uncertain significance (Dec 11, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001354762.5 First in ClinVar: Jun 22, 2020 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 21839045‚ 27532257‚ 31983221‚ 33302605 Comment: show This missense variant replaces alanine with threonine at codon 774 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy, including two related individuals who were diagnosed in the neonatal period (PMID: 21839045, 27532257, 33302605). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 43/1551002 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

Uncertain significance (Jun 01, 2014) C Contributing to aggregate classification	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Cardiomyopathy, hypertrophic (Autosomal dominant inheritance)	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190402.2 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript	Publications: PubMed (1) PubMed: 25637381 Comment: show Low GERP score may suggest that this variant may belong in a lower pathogenicity class (less) Observation: 1 Collection method: research Allele origin: germline Affected status: unknown Observation 1 Collection method: research Allele origin: germline Affected status: unknown

Uncertain significance (Sep 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Fulgent Genetics, Fulgent Genetics Accession: SCV002815188.1 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 (Jun 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059135.6 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (1) PubMed: 21839045 Comment: show The p.Ala774Thr variant in MYBPC3 has been reported in at least 3 individuals with hypertrophic cardiomyopathy and segregated with disease in 2 affected individuals from 1 family (Maron 2012 PMID: 21839045, Walsh 2017 PMID: 27532257, Fernlund 2020 PMID: 33302605 ), as well as in 1 individual with dilated cardiomyopathy (Mazzarotto 2020 PMID: 31983221). It has also been identified in 2/57196 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 42618). 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: PM2_P, PS4_P, BP4. (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 31, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004939693.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024	Comment: show The c.2320G>A (p.A774T) alteration is located in exon 24 (coding exon 24) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2320, causing the alanine (A) at amino acid position 774 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, 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 (Aug 13, 2015) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015)	Left ventricular noncompaction 10	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000493758.1 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Uncertain significance (Aug 13, 2015) N Not contributing to aggregate classification	no assertion criteria provided (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	Knight Diagnostic Laboratories, Oregon Health and Sciences University Study: CSER-NextGen Accession: SCV000493759.1 First in ClinVar: Jan 23, 2017 Last updated: Jan 23, 2017	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests that this missense variant does not alter protein structure/function; Reported in association with HCM in published literature (PMID: 21839045, 27532257, 33302605); This variant is associated with the following publications: (PMID: 27532257, 23299917, 25637381, 34426522, 37652022, 33302605, 21839045)

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 774 of the MYBPC3 protein (p.Ala774Thr). This variant is present in population databases (rs368104687, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 21839045, 27532257, 33302605). ClinVar contains an entry for this variant (Variation ID: 42618). 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 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:

This missense variant replaces alanine with threonine at codon 774 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy, including two related individuals who were diagnosed in the neonatal period (PMID: 21839045, 27532257, 33302605). It has also been reported in an individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 2/152072 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 missense variant replaces alanine with threonine at codon 774 of the MYBPC3 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in five individuals affected with hypertrophic cardiomyopathy, including two related individuals who were diagnosed in the neonatal period (PMID: 21839045, 27532257, 33302605). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 31983221). This variant has been identified in 43/1551002 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:

The p.Ala774Thr variant in MYBPC3 has been reported in at least 3 individuals with hypertrophic cardiomyopathy and segregated with disease in 2 affected individuals from 1 family (Maron 2012 PMID: 21839045, Walsh 2017 PMID: 27532257, Fernlund 2020 PMID: 33302605 ), as well as in 1 individual with dilated cardiomyopathy (Mazzarotto 2020 PMID: 31983221). It has also been identified in 2/57196 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 42618). 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: PM2_P, PS4_P, BP4.

Comment:

The c.2320G>A (p.A774T) alteration is located in exon 24 (coding exon 24) of the MYBPC3 gene. This alteration results from a G to A substitution at nucleotide position 2320, causing the alanine (A) at amino acid position 774 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Hereditary Hypertrophic Cardiomyopathy in Children and Young Adults-The Value of Reevaluating and Expanding Gene Panel Analyses.	Fernlund E	Genes	2020	PMID: 33302605
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
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

Text-mined citations for rs368104687 ...

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 Apr 13, 2026