VCV000008616.25 - ClinVar

NM_000256.3(MYBPC3):c.3286G>T (p.Glu1096Ter)

Germline

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.

(12)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000256.3(MYBPC3):c.3286G>T (p.Glu1096Ter)

Variation ID: 8616 Accession: VCV000008616.25

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p11.2 11: 47333238 (GRCh38) [ NCBI UCSC ] 11: 47354789 (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 4, 2013	Nov 24, 2024	Jan 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000256.3:c.3286G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000247.2:p.Glu1096Ter	nonsense
NC_000011.10:g.47333238C>A
NC_000011.9:g.47354789C>A
NG_007667.1:g.24465G>T
LRG_386:g.24465G>T
LRG_386t1:c.3286G>T	LRG_386p1:p.Glu1096Ter

... more HGVS ... less HGVS

Protein change

E1096*

Other names

p.E1096*:GAG>TAG
p.Glu1096*

Canonical SPDI

NC_000011.10:47333237:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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

Links

ClinGen: CA013793 OMIM: 600958.0014 dbSNP: rs121909377 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	3971	3990

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	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 25, 2018	RCV000009147.9
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 18, 2024	RCV000158223.11
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Mar 3, 2022	RCV000621059.2
Hypertrophic cardiomyopathy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 28, 2023	RCV000628863.14
Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10	Pathogenic (1)	criteria provided, single submitter	Oct 15, 2021	RCV002496311.1
Cardiomyopathy	Pathogenic (1)	criteria provided, single submitter	Jul 8, 2022	RCV003486544.1

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.	More information 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 (-)	criteria provided, single submitter (LGCM Criteria August 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratory of Genetics and Molecular Cardiology, University of São Paulo Study: Sarcomeric Human Cardiomyopathy Registry (ShaRe) Accession: SCV000256169.1 First in ClinVar: Nov 04, 2015 Last updated: Nov 04, 2015	Publications: PubMed (3) PubMed: 12601548‚ 10424815‚ 12707239 Number of individuals with the variant: 1
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: yes Allele origin: germline	Center for Human Genetics, University of Leuven Accession: SCV000886769.1 First in ClinVar: May 02, 2019 Last updated: May 02, 2019
Pathogenic (Jul 03, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Hypertrophic cardiomyopathy (Autosomal dominant inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000059223.5 First in ClinVar: May 03, 2013 Last updated: Jun 01, 2016	Publications: PubMed (5) PubMed: 10424815‚ 12601548‚ 12707239‚ 27532257‚ 24093860 Comment: The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in … (more) The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in MYH7 (Richard 1999, Richard 2003, Marsiglia 2013, Walsh 2016, LMM data). The p.Glu1096X variant was observed in isolation in 3 affected relatives (including an obligate carrier) an d in combination with the MYH7 variant in 1 affected relative. The proband and t he relative, who both carry the MYH7 and this variant, exhibited more severe dis ease compared with the other affected relatives. This variant has been identifie d in 1/11,964 African chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs121909377). This nonsense variant leads to a premature termination codon at position 1096, which is predicted to lead t o a truncated or absent protein. In summary, this variant meets criteria to be c lassified as pathogenic for HCM in an autosomal dominant manner based upon the p redicted impact of the variant, segregation studies, and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1. (less) Number of individuals with the variant: 3
Pathogenic (Jul 08, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiomyopathy Affected status: unknown Allele origin: germline	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario Accession: SCV004239377.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024
Pathogenic (Apr 25, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Affected status: unknown Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV000840019.1 First in ClinVar: May 30, 2018 Last updated: May 30, 2018	Comment: This c.3286G>T (p.Glu1096) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely … (more) This c.3286G>T (p.Glu1096) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely low allele frequency in general population according to gnomad database. It has been demonstrated that this variant was co-segregated with disease in a HCM family [PMID: 10424815]. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene is classified as pathogenic. (less)
Pathogenic (Mar 03, 2022)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000740203.4 First in ClinVar: Apr 14, 2018 Last updated: Nov 29, 2022	Publications: PubMed (3) PubMed: 10424815‚ 24093860‚ 27532257 Comment: The p.E1096* pathogenic mutation (also known as c.3286G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at … (more) The p.E1096* pathogenic mutation (also known as c.3286G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3286. This changes the amino acid from a glutamic acid to a stop codon within coding exon 30. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less) Number of individuals with the variant: 1
Pathogenic (Oct 15, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypertrophic cardiomyopathy 4 Left ventricular noncompaction 10 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807190.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Oct 28, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Hypertrophic cardiomyopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000749771.8 First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024	Publications: PubMed (4) PubMed: 28492532‚ 19574547‚ 10424815‚ 27532257 Comment: This sequence change creates a premature translational stop signal (p.Glu1096) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu1096) 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). 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 premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8616). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 18, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000208158.16 First in ClinVar: Feb 24, 2015 Last updated: Sep 16, 2024	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of … (more) Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Found independently in three affected individuals from a French Caribbean family with HCM, including an obligate carrier, and co-occurred with a missense variant in the MYH7 gene in two affected relatives with more severe disease (PMID: 10424815); This variant is associated with the following publications: (PMID: 28193612, 12601548, 31447099, 12707239, 24093860, 27532257, 18761664, 20031583, 31513939, 32009526, 34542152, 10424815) (less)
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413978.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (10) PubMed: 10424815‚ 12601548‚ 12707239‚ 24093860‚ 27532257‚ 28193612‚ 31447099‚ 31513939‚ 32009526‚ 34542152 Comment: PP1, PM2, PS4_moderate, PVS1 Number of individuals with the variant: 2
Pathogenic (Jul 01, 1999)	no assertion criteria provided Method: literature only	CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 4 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029364.2 First in ClinVar: Apr 04, 2013 Last updated: Aug 05, 2019	Publications: PubMed (2) PubMed: 7786104‚ 10424815 Hengstenberg, C., Charron, P., (more...) Hengstenberg, C., Charron, P., Beckmann, J. S., Weissenbach, J., Isnard, R., Komajda, M., Schwartz, K. Evidence for the existence of a fifth gene causing familial hypertrophic cardiomyopathy. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A1013-only, 1993. Comment on evidence: In a family with hypertrophic cardiomyopathy (CMH4; 115197), previously reported by Hengstenberg et al. (1993, 1994), Richard et al. (1999) found that of 8 affected … (more) In a family with hypertrophic cardiomyopathy (CMH4; 115197), previously reported by Hengstenberg et al. (1993, 1994), Richard et al. (1999) found that of 8 affected members, 2 had a G-to-T mutation at codon 1096 of the MYBPC3 gene, leading to a TAA termination codon (E1096X); 4 had a G-to-A transition in exon 15 of the MYH7 gene (160760.0033) and 2 were doubly heterozygous for the 2 mutations. The E1096X mutation was predicted to produce a truncated protein without the C-terminal domain, which binds to titin and myosin. (less)
Pathogenic (Sep 16, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: research	not provided Affected status: yes Allele origin: germline	Gharavi Laboratory, Columbia University Accession: SCV000809464.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
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Comment:

The p.Glu1096X variant in MYBPC3 has been reported in 7 individuals with HCM, in cluding 1 individual with HCM who also carries a variant in MYH7 (Richard 1999, Richard 2003, Marsiglia 2013, Walsh 2016, LMM data). The p.Glu1096X variant was observed in isolation in 3 affected relatives (including an obligate carrier) an d in combination with the MYH7 variant in 1 affected relative. The proband and t he relative, who both carry the MYH7 and this variant, exhibited more severe dis ease compared with the other affected relatives. This variant has been identifie d in 1/11,964 African chromosomes by the Genome Aggregation Database (gnomAD, ht tp://gnomad.broadinstitute.org/; dbSNP rs121909377). This nonsense variant leads to a premature termination codon at position 1096, which is predicted to lead t o a truncated or absent protein. In summary, this variant meets criteria to be c lassified as pathogenic for HCM in an autosomal dominant manner based upon the p redicted impact of the variant, segregation studies, and absence from controls. ACMG/AMP Criteria applied: PVS1; PM2; PS4_Moderate; PP1.

Comment:

This c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene has been reported in multiple hypertrophic cardiomyopathy (HMC) patients [PMID: 7786104, 10424815, 12707239] while observed with extremely low allele frequency in general population according to gnomad database. It has been demonstrated that this variant was co-segregated with disease in a HCM family [PMID: 10424815]. This variant has been reported by multiple clinical test center as disease-causing according to ClinVar database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on current evidences, this c.3286G>T (p.Glu1096*) variant in the MYBPC3 gene is classified as pathogenic.

Comment:

The p.E1096* pathogenic mutation (also known as c.3286G>T), located in coding exon 30 of the MYBPC3 gene, results from a G to T substitution at nucleotide position 3286. This changes the amino acid from a glutamic acid to a stop codon within coding exon 30. This alteration has been reported in multiple unrelated individuals with hypertrophic cardiomyopathy (Richard P et al. J. Med. Genet., 1999 Jul;36:542-5; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change creates a premature translational stop signal (p.Glu1096*) 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). 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 premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 10424815, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8616). For these reasons, this variant has been classified as Pathogenic.

Comment:

Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Found independently in three affected individuals from a French Caribbean family with HCM, including an obligate carrier, and co-occurred with a missense variant in the MYH7 gene in two affected relatives with more severe disease (PMID: 10424815); This variant is associated with the following publications: (PMID: 28193612, 12601548, 31447099, 12707239, 24093860, 27532257, 18761664, 20031583, 31513939, 32009526, 34542152, 10424815)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.	Park J	Human molecular genetics	2022	PMID: 34542152
Pathogenic and Uncertain Genetic Variants Have Clinical Cardiac Correlates in Diverse Biobank Participants.	Pottinger TD	Journal of the American Heart Association	2020	PMID: 32009526
Clinical and ECG variables to predict the outcome of genetic testing in hypertrophic cardiomyopathy.	Robyns T	European journal of medical genetics	2020	PMID: 31513939
Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.	eMERGE Consortium. Electronic address: [email protected]	American journal of human genetics	2019	PMID: 31447099
Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic Cardiomyopathy.	Weissler-Snir A	Circulation. Cardiovascular imaging	2017	PMID: 28193612
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
Screening of MYH7, MYBPC3, and TNNT2 genes in Brazilian patients with hypertrophic cardiomyopathy.	Marsiglia JD	American heart journal	2013	PMID: 24093860
Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency.	Marston S	Circulation research	2009	PMID: 19574547
Hypertrophic cardiomyopathy: distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy.	Richard P	Circulation	2003	PMID: 12707239
Molecular genetics of familial hypertrophic cardiomyopathy (FHC).	Bashyam MD	Journal of human genetics	2003	PMID: 12601548
Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy.	Richard P	Journal of medical genetics	1999	PMID: 10424815
[Demonstration of a fifth locus implicated in familial hypertrophic cardiomyopathies].	Hengstenberg C	Archives des maladies du coeur et des vaisseaux	1994	PMID: 7786104
Hengstenberg, C., Charron, P., Beckmann, J. S., Weissenbach, J., Isnard, R., Komajda, M., Schwartz, K. Evidence for the existence of a fifth gene causing familial hypertrophic cardiomyopathy. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A1013-only, 1993.	-	-	-	-
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Text-mined citations for rs121909377 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000256.3(MYBPC3):c.3286G>T (p.Glu1096Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121909377 ...