VCV000177949.60 - ClinVar

NM_000256.3(MYBPC3):c.2671C>T (p.Arg891Trp)

Germline

Classification

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

Uncertain significance
Uncertain significance (10)

10 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.2671C>T (p.Arg891Trp)

Variation ID: 177949 Accession: VCV000177949.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47335943 (GRCh38) [ NCBI UCSC ] 11: 47357494 (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	Apr 9, 2018	Aug 16, 2026	Jan 22, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2671C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg891Trp	missense
NC_000011.10:g.47335943G>A
NC_000011.9:g.47357494G>A
NG_007667.1:g.21760C>T
LRG_386:g.21760C>T
LRG_386t1:c.2671C>T	LRG_386p1:p.Arg891Trp

... more HGVS ... less HGVS

Protein change

R891W

Other names

Canonical SPDI

NC_000011.10:47335942: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.

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA012818 dbSNP: rs727504418 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	May 15, 2019	RCV000154612.8
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 20, 2025	RCV000628920.10
not provided	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Feb 6, 2024	RCV001200341.40
Cardiomyopathy	Uncertain significance (1)	criteria provided, single submitter	Jul 25, 2025	RCV001526058.6
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Oct 29, 2025	RCV002426741.4
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Apr 1, 2022	RCV002483339.2
Hypertrophic cardiomyopathy 4	Uncertain significance (1)	criteria provided, single submitter	Jan 22, 2026	RCV006704580.1

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 (Apr 01, 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: SCV002786237.1 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 (Feb 06, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV005079592.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Comment: show In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 32183154, 31447099, Murakami2014, Maeda2009, 32600061, 25611685) (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 (May 15, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000204285.5 First in ClinVar: Jan 31, 2015 Last updated: Jul 03, 2020	Publications: PubMed (1) PubMed: 25611685 Comment: show Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg891Trp variant in MYBPC3 has been reported in 1 individual with DCM (Maeda 2009) and as a de novo occurrence in 1 infant with HCM (Alfares 2015, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177949) and has been identified in 3/14552 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg891Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg891Trp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM6, PP3. (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: 3

Uncertain Significance (Feb 05, 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: SCV004836734.1 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: 25611685‚ 27532257‚ 32183154‚ 33495597 Comment: show This missense variant replaces arginine with tryptophan at codon 891 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: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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: 4 Zygosity: 4 Single Heterozygotes

Uncertain significance (Jun 27, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV004236663.2 First in ClinVar: Feb 04, 2024 Last updated: Sep 06, 2025	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 (Oct 29, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002743873.3 First in ClinVar: Nov 29, 2022 Last updated: Jan 11, 2026	Comment: show The c.2671C>T (p.R891W) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2671, causing the arginine (R) at amino acid position 891 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (6/221382) total alleles studied. The highest observed frequency was 0.02% (3/15030) of East Asian alleles. 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 (Jul 25, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV001736329.4 First in ClinVar: Jun 19, 2021 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 25611685‚ 27532257‚ 32183154‚ 33495597 Comment: show This missense variant replaces arginine with tryptophan at codon 891 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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 (Dec 20, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000749828.6 First in ClinVar: May 28, 2018 Last updated: Mar 07, 2026	Publications: PubMed (4) PubMed: 25611685‚ 27532257‚ 32183154‚ 32600061 Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 891 of the MYBPC3 protein (p.Arg891Trp). 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 individual(s) with MYBPC3-related conditions (PMID: 25611685, 27532257, 32183154, 32600061). ClinVar contains an entry for this variant (Variation ID: 177949). 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

Uncertain significance (Jan 22, 2026) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy 4	3billion Accession: SCV007609920.1 First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026	Publications: PubMed (1) PubMed: 25611685 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.51 (damaging >=0.6, benign <0.4), 3Cnet: 0.01 (damaging >0.75, benign <0.1)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 25611685). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25611685). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

Uncertain significance (Jun 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001371273.37 First in ClinVar: Jul 16, 2020 Last updated: Jul 27, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Uncertain significance (Sep 24, 2025) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Dasa Accession: SCV007662985.1 First in ClinVar: Aug 16, 2026 Last updated: Aug 16, 2026	Comment: show NM_000256.3(MYBPC3):c.2671C>T (p.Arg891Trp) is a missense variant that results in the substitution of arginine with tryptophan. This variant is rare in population databases. Computational prediction algorithms are consistent with a deleterious effect. The currently available literature and clinical evidence are not sufficient to establish a definitive association between this variant and the reported condition. Therefore, this variant is 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:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 32183154, 31447099, Murakami2014, Maeda2009, 32600061, 25611685)

Comment:

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg891Trp variant in MYBPC3 has been reported in 1 individual with DCM (Maeda 2009) and as a de novo occurrence in 1 infant with HCM (Alfares 2015, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177949) and has been identified in 3/14552 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg891Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg891Trp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM6, PP3.

Comment:

This missense variant replaces arginine with tryptophan at codon 891 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: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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 c.2671C>T (p.R891W) alteration is located in exon 26 (coding exon 26) of the MYBPC3 gene. This alteration results from a C to T substitution at nucleotide position 2671, causing the arginine (R) at amino acid position 891 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.003% (6/221382) total alleles studied. The highest observed frequency was 0.02% (3/15030) of East Asian alleles. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Comment:

This missense variant replaces arginine with tryptophan at codon 891 of the MYBPC3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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 arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 891 of the MYBPC3 protein (p.Arg891Trp). 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 individual(s) with MYBPC3-related conditions (PMID: 25611685, 27532257, 32183154, 32600061). ClinVar contains an entry for this variant (Variation ID: 177949). 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 variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Damaging effect on gene or gene product predicted by in silico programs is uncertain [REVEL: 0.51 (damaging >=0.6, benign <0.4), 3Cnet: 0.01 (damaging >0.75, benign <0.1)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with MYBPC3-related disorder (PMID: 25611685). The variant has been previously reported as de novo in a similarly affected individual (PMID: 25611685). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Comment:

NM_000256.3(MYBPC3):c.2671C>T (p.Arg891Trp) is a missense variant that results in the substitution of arginine with tryptophan. This variant is rare in population databases. Computational prediction algorithms are consistent with a deleterious effect. The currently available literature and clinical evidence are not sufficient to establish a definitive association between this variant and the reported condition. Therefore, this variant is classified as a variant of uncertain significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Increased Burden of Ion Channel Gene Variants Is Related to Distinct Phenotypes in Pediatric Patients With Left Ventricular Noncompaction.	Hirono K	Circulation. Genomic and precision medicine	2020	PMID: 32600061
Left Ventricular Noncompaction and Congenital Heart Disease Increases the Risk of Congestive Heart Failure.	Hirono K	Journal of clinical medicine	2020	PMID: 32183154
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

Text-mined citations for rs727504418 ...

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 Aug 16, 2026