VCV000802674.5 - ClinVar

NM_000256.3(MYBPC3):c.2504G>T (p.Arg835Leu)

Germline

Classification

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

Uncertain significance
Uncertain significance (3)

3 out of 3 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.2504G>T (p.Arg835Leu)

Variation ID: 802674 Accession: VCV000802674.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337489 (GRCh38) [ NCBI UCSC ] 11: 47359040 (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	Jan 11, 2020	Dec 14, 2024	Sep 23, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2504G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg835Leu	missense
NC_000011.10:g.47337489C>A
NC_000011.9:g.47359040C>A
NG_007667.1:g.20214G>T
LRG_386:g.20214G>T
LRG_386t1:c.2504G>T	LRG_386p1:p.Arg835Leu

... more HGVS ... less HGVS

Protein change

R835L

Other names

Canonical SPDI

NC_000011.10:47337488: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.

0.00040 (A)

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

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD) 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00005

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Links

ClinGen: CA078769 dbSNP: rs527305885 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	4724	4746

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 4	Uncertain significance (1)	criteria provided, single submitter	May 28, 2019	RCV000988541.1
Hypertrophic cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Sep 23, 2024	RCV001293107.4

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 (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Hypertrophic cardiomyopathy 4	Mendelics Accession: SCV001138296.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020	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 (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy	Genetics and Genomics Program, Sidra Medicine Accession: SCV001434095.1 First in ClinVar: Feb 28, 2021 Last updated: Feb 28, 2021	Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Test name: Trusight Cardio Sequencing Platform type: next-gen sequencing

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: SCV004830698.2 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 (8) PubMed: 20624503‚ 20800588‚ 22112859‚ 22989827‚ 23711808‚ 27532257‚ 30606897‚ 35284542 Comment: show This missense variant replaces arginine with leucine at codon 835 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 22112859, 22989827, 23711808, 27532257, 30606897; Al-shafai 2020, dissertation, Khalifa University). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 22112859, 22989827, 30606897). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 35284542). This variant has been identified in 14/280406 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: 10 Zygosity: 10 Single Heterozygotes

Comment:

This missense variant replaces arginine with leucine at codon 835 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 individuals affected with hypertrophic cardiomyopathy (PMID: 20624503, 20800588, 22112859, 22989827, 23711808, 27532257, 30606897; Al-shafai 2020, dissertation, Khalifa University). One of these individuals also carried a different pathogenic variant in the MYBPC3 gene that could explain the observed phenotype (PMID: 22112859, 22989827, 30606897). This variant has also been reported in an individual affected with dilated cardiomyopathy (PMID: 35284542). This variant has been identified in 14/280406 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
Genetic variants in Chinese patients with sporadic dilated cardiomyopathy: a cross-sectional study.	Shen C	Annals of translational medicine	2022	PMID: 35284542
Incidence, Clinical Characteristics, and Long-term Outcome of the Dilated Phase of Hypertrophic Cardiomyopathy.	Aizawa Y	The Keio journal of medicine	2019	PMID: 30606897
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
Mutation spectrum in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy.	Liu W	The American journal of cardiology	2013	PMID: 23711808
Dilated phase of hypertrophic cardiomyopathy caused by two different sarcomere mutations, treated with surgical left ventricular reconstruction and cardiac resynchronization therapy with a defibrillator.	Sato A	Internal medicine (Tokyo, Japan)	2012	PMID: 22989827
Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy.	Otsuka H	Circulation journal : official journal of the Japanese Circulation Society	2012	PMID: 22112859
Development of a high resolution melting method for the detection of genetic variations in hypertrophic cardiomyopathy.	Millat G	Clinica chimica acta; international journal of clinical chemistry	2010	PMID: 20800588
Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy.	Millat G	European journal of medical genetics	2010	PMID: 20624503

Text-mined citations for rs527305885 ...

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 Dec 20, 2025