VCV000042641.25 - ClinVar

NC_000011.10:g.47337436del

Germline

Classification

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

Pathogenic
Pathogenic (7)

7 out of 7 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

NC_000011.10:g.47337436del

Variation ID: 42641 Accession: VCV000042641.25

Type and length

Deletion, 1 bp

Location

Cytogenetic: 11p11.2 11: 47337435 (GRCh38) [ NCBI UCSC ] 11: 47358986 (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	Oct 22, 2016	Feb 15, 2026	Jan 15, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.2558delG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		frameshift
NC_000011.10:g.47337436del
NC_000011.9:g.47358987del
NG_007667.1:g.20268del
LRG_386:g.20268del
LRG_386t1:c.2558del	LRG_386p1:p.Gly853fs

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000011.10:47337434:CC:C

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: CA012641 dbSNP: rs397515977 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	4728	4750

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 provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 15, 2026	RCV000158367.13
Hypertrophic cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 4, 2024	RCV000473384.16
Cardiomyopathy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 24, 2024	RCV003486549.2
Hypertrophic cardiomyopathy 4	Pathogenic (1)	criteria provided, single submitter	Mar 12, 2024	RCV005401294.1

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.
Pathogenic (Dec 04, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Hypertrophic cardiomyopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000546432.11 First in ClinVar: Apr 17, 2017 Last updated: Feb 15, 2026	Publications: PubMed (3) PubMed: 19574547‚ 26914223‚ 27532257 Comment: show This sequence change creates a premature translational stop signal (p.Gly853Alafs*26) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42641). For these reasons, this variant has been classified as 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

Pathogenic (May 10, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Cardiomyopathy	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239364.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	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 (Nov 04, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hypertrophic cardiomyopathy (Autosomal dominant inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059159.6 First in ClinVar: May 03, 2013 Last updated: Apr 20, 2024	Publications: PubMed (2) PubMed: 15519027‚ 24793961 Comment: show The Gly853fs variant in MYBPC3 has been reported in one individual with HCM and was absent from 200 Caucasian and 200 Black control chromosomes (Van Driest 2004 - reported as I852fs/25, Bos 2014). This variant has also been identified by our laboratory in 2 Caucasian adults with HCM and segregated with disease in 2 affected relatives from one family. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 853 and leads to a premature termination codon 26 amino acids downstream. This alteration 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 in patients with HCM. In summary, this variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/lmm) based on the severity of the predicted impact. (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

Pathogenic (Dec 24, 2024) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Cardiomyopathy	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005884566.1 First in ClinVar: Mar 16, 2025 Last updated: Mar 16, 2025	Publications: PubMed (2) PubMed: 15519027‚ 26914223 Comment: show Variant summary: MYBPC3 c.2558delG (p.Gly853AlafsX26) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2558delG has been reported in the literature in at-least one individual affected with Cardiomyopathy (example, Murphy_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26914223, 15519027). ClinVar contains an entry for this variant (Variation ID: 42641). Based on the evidence outlined above, the variant was classified as 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

Pathogenic (Jan 17, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	not provided	Blueprint Genetics Accession: SCV000928177.1 First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 Comment: Patient analyzed with Hypertrophic Cardiomyopathy (HCM) Panel	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 (Mar 12, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Hypertrophic cardiomyopathy 4	Illumina Laboratory Services, Illumina Accession: SCV006059906.1 First in ClinVar: May 03, 2025 Last updated: May 03, 2025	Publications: PubMed (2) PubMed: 27532257‚ 30327538 Comment: show The MYBPC3 c.2558del p.(Gly853AlafsTer26) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 27532257; 30327538). This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. Based on the available evidence, this variant is classified as pathogenic for hypertrophic cardiomyopathy. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jan 15, 2026) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000208302.18 First in ClinVar: Feb 24, 2015 Last updated: Feb 07, 2026	Comment: show Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in multiple patients with HCM referred for genetic testing at GeneDx and in the published literature (PMID: 15519027, 24793961, 26914223, 27532257, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26914223, 15519027, 24793961, 27532257, 28420666, 34135346, 37652022, 36243179) (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

Comment:

This sequence change creates a premature translational stop signal (p.Gly853Alafs*26) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 26914223, 27532257). ClinVar contains an entry for this variant (Variation ID: 42641). For these reasons, this variant has been classified as Pathogenic.

Comment:

The Gly853fs variant in MYBPC3 has been reported in one individual with HCM and was absent from 200 Caucasian and 200 Black control chromosomes (Van Driest 2004 - reported as I852fs/25, Bos 2014). This variant has also been identified by our laboratory in 2 Caucasian adults with HCM and segregated with disease in 2 affected relatives from one family. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 853 and leads to a premature termination codon 26 amino acids downstream. This alteration 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 in patients with HCM. In summary, this variant meets our criteria to be classified as pathogenic (www.partners.org/personalizedmedicine/lmm) based on the severity of the predicted impact.

Comment:

Variant summary: MYBPC3 c.2558delG (p.Gly853AlafsX26) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2558delG has been reported in the literature in at-least one individual affected with Cardiomyopathy (example, Murphy_2016) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26914223, 15519027). ClinVar contains an entry for this variant (Variation ID: 42641). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The MYBPC3 c.2558del p.(Gly853AlafsTer26) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with hypertrophic cardiomyopathy (PMID: 27532257; 30327538). This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. Based on the available evidence, this variant is classified as pathogenic for hypertrophic cardiomyopathy.

Comment:

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Identified in multiple patients with HCM referred for genetic testing at GeneDx and in the published literature (PMID: 15519027, 24793961, 26914223, 27532257, 37652022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26914223, 15519027, 24793961, 27532257, 28420666, 34135346, 37652022, 36243179)

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Psychological adaptation to molecular autopsy findings following sudden cardiac death in the young.	Bates K	Genetics in medicine : official journal of the American College of Medical Genetics	2019	PMID: 30327538
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
Evaluation of the Mayo Clinic Phenotype-Based Genotype Predictor Score in Patients with Clinically Diagnosed Hypertrophic Cardiomyopathy.	Murphy SL	Journal of cardiovascular translational research	2016	PMID: 26914223
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
Myosin binding protein C mutations and compound heterozygosity in hypertrophic cardiomyopathy.	Van Driest SL	Journal of the American College of Cardiology	2004	PMID: 15519027

Text-mined citations for rs397515977 ...

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 Feb 15, 2026