VCV000042714.11 - ClinVar

NM_000256.3(MYBPC3):c.3476_3479dup (p.Pro1161fs)

Germline

Classification

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

Pathogenic
Pathogenic (4)

4 out of 4 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.3476_3479dup (p.Pro1161fs)

Variation ID: 42714 Accession: VCV000042714.11

Type and length

Duplication, 4 bp

Location

Cytogenetic: 11p11.2 11: 47332824-47332825 (GRCh38) [ NCBI UCSC ] 11: 47354375-47354376 (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 30, 2015	Mar 7, 2026	May 18, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3476_3479dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Pro1161fs	frameshift
NM_000256.3:c.3476_3479dupTTAT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NC_000011.10:g.47332826_47332829dup
NC_000011.9:g.47354377_47354380dup
NG_007667.1:g.24875_24878dup
LRG_386:g.24875_24878dup
LRG_386t1:c.3476_3479dup	LRG_386p1:p.Pro1161fs

... more HGVS ... less HGVS

Protein change

P1161fs

Other names

p.Pro1161TyrfsX9

Canonical SPDI

NC_000011.10:47332824:ATAAA:ATAAATAAA

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: CA261323 dbSNP: rs397516019 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	4829	4851

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	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	May 18, 2022	RCV000035589.10
not provided	Pathogenic (1)	criteria provided, single submitter	May 29, 2013	RCV000158404.1
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Nov 11, 2021	RCV003149619.2

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.
Pathogenic (May 29, 2013) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	not provided	GeneDx Accession: SCV000208339.4 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015	Comment: show Although the c.3476_3479dupTTAT variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 1161, changing it to a Tyrosine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Pro1161TyrfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.3476_3479dupTTAT in the MYBPC3 gene is interpreted as a pathogenic variant. (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

Pathogenic (Jun 02, 2011) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Hypertrophic cardiomyopathy	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059240.5 First in ClinVar: May 03, 2013 Last updated: Jan 30, 2015	Comment: show The Pro1161fs variant has not been reported in the literature but has been detec ted in 1 individual with HCM tested by our laboratory. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1161 and leads to a premature stop codon 8 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein (loss of function ). Loss of function is an established mechanism of disease for the MYBPC3 gene, which makes it highly likely that the Pro1161fs variant is pathogenic. (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

Pathogenic (Nov 11, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV003838929.1 First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023	Publications: PubMed (1) PubMed: 25741868 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (May 18, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003270418.4 First in ClinVar: Feb 07, 2023 Last updated: Mar 07, 2026	Publications: PubMed (3) PubMed: 19574547‚ 24793961‚ 27532257 Comment: show ClinVar contains an entry for this variant (Variation ID: 42714). For these reasons, this variant has been classified as Pathogenic. This variant is also known as as c.3476-3479dupTTAT (p.Ile1160Ilefs10). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1161Tyrfs9) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). (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:

Although the c.3476_3479dupTTAT variant in the MYBPC3 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Proline 1161, changing it to a Tyrosine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Pro1161TyrfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.3476_3479dupTTAT in the MYBPC3 gene is interpreted as a pathogenic variant.

Comment:

The Pro1161fs variant has not been reported in the literature but has been detec ted in 1 individual with HCM tested by our laboratory. It is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1161 and leads to a premature stop codon 8 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein (loss of function ). Loss of function is an established mechanism of disease for the MYBPC3 gene, which makes it highly likely that the Pro1161fs variant is pathogenic.

Comment:

ClinVar contains an entry for this variant (Variation ID: 42714). For these reasons, this variant has been classified as Pathogenic. This variant is also known as as c.3476-3479dupTTAT (p.Ile1160Ilefs*10). This premature translational stop signal has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro1161Tyrfs*9) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547).

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	Richards S	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25741868
Characterization of a phenotype-based genetic test prediction score for unrelated patients with hypertrophic cardiomyopathy.	Bos JM	Mayo Clinic proceedings	2014	PMID: 24793961
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547

Text-mined citations for rs397516019 ...

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 Mar 08, 2026