VCV000164032.30 - ClinVar

NM_000256.3(MYBPC3):c.3613C>T (p.Arg1205Trp)

Germline

Classification

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

Conflicting classifications of pathogenicity
Likely pathogenic (2); Uncertain significance (8)

10 out of 13 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.3613C>T (p.Arg1205Trp)

Variation ID: 164032 Accession: VCV000164032.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47332580 (GRCh38) [ NCBI UCSC ] 11: 47354131 (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	Feb 27, 2016	Mar 7, 2026	Dec 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3613C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Arg1205Trp	missense
NC_000011.10:g.47332580G>A
NC_000011.9:g.47354131G>A
NG_007667.1:g.25123C>T
LRG_386:g.25123C>T
LRG_386t1:c.3613C>T	LRG_386p1:p.Arg1205Trp

... more HGVS ... less HGVS

Protein change

R1205W

Other names

p.R1205W:CGG>TGG

Canonical SPDI

NC_000011.10:47332579: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), exomes 0.00000

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

Links

ClinGen: CA014469 dbSNP: rs727503171 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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Nov 10, 2014	RCV000151066.6
Primary familial hypertrophic cardiomyopathy	no classifications from unflagged records (1)	no classifications from unflagged records	Nov 8, 2022	RCV000208211.2
Hypertrophic cardiomyopathy	Likely pathogenic (1)	criteria provided, single submitter	Dec 8, 2025	RCV000263553.11
Left ventricular noncompaction 10	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000377792.5
Hypertrophic cardiomyopathy 4	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 13, 2018	RCV000604457.6
Cardiomyopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 9, 2024	RCV001171124.4
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Jul 1, 2025	RCV001729409.9
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Mar 21, 2024	RCV002453487.3

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.
Likely pathogenic (Dec 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000828899.8 First in ClinVar: Oct 10, 2018 Last updated: Mar 07, 2026	Publications: PubMed (9) PubMed: 24793961‚ 27532257‚ 28492532‚ 30206291‚ 30775854‚ 31931689‚ 33495596‚ 33673806‚ 37652022 Comment: show This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1205 of the MYBPC3 protein (p.Arg1205Trp). This variant is present in population databases (rs727503171, gnomAD 0.0009%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 30206291, 30775854, 31931689, 33495596, 33673806, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 164032). 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 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 (Sep 21, 2015) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Guidelines, 2013)	Hypertrophic cardiomyopathy 4	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV000745026.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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 (Mar 19, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV001333804.2 First in ClinVar: May 31, 2020 Last updated: Dec 29, 2021	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 (Sep 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005412318.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (6) PubMed: 24793961‚ 27532257‚ 31931689‚ 33673806‚ 35653365‚ 37652022 Comment: show PM2, PS4_moderate (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 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208181.15 First in ClinVar: Feb 24, 2015 Last updated: Jul 13, 2025	Comment: show Not observed at significant frequency in large population cohorts (gnomAD); 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, 31931689, 30206291, 33673806, 35653365, 24793961, 37652022, 30775854, 37477868, 32841044, 33495596, 38489124, 33495597) (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 (Nov 10, 2014) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000198805.4 First in ClinVar: Feb 02, 2015 Last updated: Oct 09, 2016	Publications: PubMed (1) PubMed: 24793961 Comment: show The p.Arg1205Trp variant in MYBPC3 has been reported in 1 individual with HCM (B os 2014) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.Arg1205Trp 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: 1

Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hypertrophic cardiomyopathy 4	Illumina Laboratory Services, Illumina Accession: SCV000372282.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (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 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Left ventricular noncompaction 10	Illumina Laboratory Services, Illumina Accession: SCV000372284.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (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 (Mar 21, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002616676.3 First in ClinVar: Nov 29, 2022 Last updated: Aug 11, 2024	Publications: PubMed (8) PubMed: 24793961‚ 27532257‚ 30206291‚ 30775854‚ 33495597‚ 33673806‚ 35653365‚ 37477868 Comment: show The p.R1205W variant (also known as c.3613C>T), located in coding exon 32 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3613. The arginine at codon 1205 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Walsh R et al. Genet Med, 2017 02;19:192-203; Inagaki N et al. J Hum Genet, 2018 Dec;63:1273-1276; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Harper AR et al. Nat Genet, 2021 02;53:135-142; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 (Apr 09, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	Color Diagnostics, LLC DBA Color Health Accession: SCV006064239.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Publications: PubMed (11) PubMed: 24793961‚ 27532257‚ 30206291‚ 30775854‚ 31931689‚ 32841044‚ 33495596‚ 33495597‚ 33673806‚ 37477868‚ 38489124 Comment: show This missense variant replaces arginine with tryptophan at codon 1205 of the MYBPC3 protein. Computational prediction tools indicate that this variant has 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 30206291, 30775854, 32841044, 33495596, 33495597, 33673806, 38489124). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 31931689) and in one individual affected with an unspecified cardiomyopathy (PMID: 37477868). This variant has been identified in 1/248370 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 (-) N Not contributing to aggregate classification	no assertion criteria provided	Hypertrophic cardiomyopathy 4	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV000733026.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	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 (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001979452.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Oct 09, 2015) N Not contributing to aggregate classification	Flagged submission flagged submission (Variant Classification) Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Primary familial hypertrophic cardiomyopathy	Blueprint Genetics Accession: SCV000264041.2 First in ClinVar: Feb 27, 2016 Last updated: Feb 27, 2016	Publications: PubMed (1) PubMed: 24793961 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

Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more

Comment:

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1205 of the MYBPC3 protein (p.Arg1205Trp). This variant is present in population databases (rs727503171, gnomAD 0.0009%). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 30206291, 30775854, 31931689, 33495596, 33673806, 37652022; internal data). ClinVar contains an entry for this variant (Variation ID: 164032). 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 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:

Not observed at significant frequency in large population cohorts (gnomAD); 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, 31931689, 30206291, 33673806, 35653365, 24793961, 37652022, 30775854, 37477868, 32841044, 33495596, 38489124, 33495597)

Comment:

The p.Arg1205Trp variant in MYBPC3 has been reported in 1 individual with HCM (B os 2014) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that this variant may impact the protein , though this information is not predictive enough to determine pathogenicity. I n summary, the clinical significance of the p.Arg1205Trp variant is uncertain.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The p.R1205W variant (also known as c.3613C>T), located in coding exon 32 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3613. The arginine at codon 1205 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Bos JM et al. Mayo Clin Proc, 2014 Jun;89:727-37; Walsh R et al. Genet Med, 2017 02;19:192-203; Inagaki N et al. J Hum Genet, 2018 Dec;63:1273-1276; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Harper AR et al. Nat Genet, 2021 02;53:135-142; Hathaway J et al. BMC Cardiovasc Disord, 2021 03;21:126). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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 arginine with tryptophan at codon 1205 of the MYBPC3 protein. Computational prediction tools indicate that this variant has 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 several individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257, 30206291, 30775854, 32841044, 33495596, 33495597, 33673806, 38489124). It has also been reported in one individual affected with dilated cardiomyopathy (PMID: 31931689) and in one individual affected with an unspecified cardiomyopathy (PMID: 37477868). This variant has been identified in 1/248370 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
Diagnostic yield from cardiac gene testing for inherited cardiac conditions and re-evaluation of pre-ACMG variants of uncertain significance.	Murphy J	Irish journal of medical science	2024	PMID: 38489124
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
Age and Sex Differences in the Genetics of Cardiomyopathy.	Akinrinade O	Journal of cardiovascular translational research	2023	PMID: 37477868
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
Common genetic variants and modifiable risk factors underpin hypertrophic cardiomyopathy susceptibility and expressivity.	Harper AR	Nature genetics	2021	PMID: 33495597
Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect.	Tadros R	Nature genetics	2021	PMID: 33495596
Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy.	Helms AS	Circulation. Genomic and precision medicine	2020	PMID: 32841044
Prospective Evaluation of the Utility of Whole Exome Sequencing in Dilated Cardiomyopathy.	Ramchand J	Journal of the American Heart Association	2020	PMID: 31931689
Genetic basis and outcome in a nationwide study of Finnish patients with hypertrophic cardiomyopathy.	Jääskeläinen P	ESC heart failure	2019	PMID: 30775854
Clinical and genetic backgrounds of hypertrophic cardiomyopathy with mid-ventricular obstruction.	Inagaki N	Journal of human genetics	2018	PMID: 30206291
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
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
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Text-mined citations for rs727503171 ...

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