chr11-47347668-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.833delG​(p.Gly278GlufsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000508 in 1,573,808 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (β˜…β˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 3.13
Variant links:
Genes affected
MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-47347668-TC-T is Pathogenic according to our data. Variant chr11-47347668-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 164140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47347668-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYBPC3NM_000256.3 linkc.833delG p.Gly278GlufsTer22 frameshift_variant Exon 8 of 35 ENST00000545968.6 NP_000247.2 Q14896-1A5YM48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYBPC3ENST00000545968.6 linkc.833delG p.Gly278GlufsTer22 frameshift_variant Exon 8 of 35 5 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkc.833delG p.Gly278GlufsTer22 frameshift_variant Exon 8 of 34 5 ENSP00000382193.2 A8MXZ9
MYBPC3ENST00000544791.1 linkn.833delG non_coding_transcript_exon_variant Exon 8 of 27 5 ENSP00000444259.1 F5GZR4

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
151924
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000107
AC:
2
AN:
186304
Hom.:
0
AF XY:
0.0000100
AC XY:
1
AN XY:
100050
show subpopulations
Gnomad AFR exome
AF:
0.0000959
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000126
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000352
AC:
5
AN:
1421884
Hom.:
0
Cov.:
33
AF XY:
0.00000284
AC XY:
2
AN XY:
703588
show subpopulations
Gnomad4 AFR exome
AF:
0.0000306
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000366
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
151924
Hom.:
1
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74212
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:6
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly278Glufs*22) 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 present in population databases (rs727503212, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). ClinVar contains an entry for this variant (Variation ID: 164140). For these reasons, this variant has been classified as Pathogenic. -

Jun 18, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is predicted to introduce a premature translation termination codon. This variant is rare in the general population database, gnomAD (2/181670). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 24793961, 27532257). This variant is reported in ClinVar (ID: 164140). Therefore, the c.833del (p.Gly278Glufs*22) variant in the MYBPC3 gene is classified as pathogenic. -

May 28, 2019
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

This variant has been identified in 1 HCM proband as part of our research program. The variant also segregated to an affected third-degree family member (3 meiosis). For further information please feel free to contact us. -

Mar 17, 2017
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 31, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The Gly278fs variant in MYBPC3 has not been reported in individuals with cardiom yopathy. Data from large population studies is insufficient to assess the freque ncy of this variant. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 278 and lead to a premature terminati on codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in MYBPC3 are established as pathogenic for HCM. In summary, this variant meets our criteria to be classifie d as pathogenic (http://pcpgm.partners.org/LMM) based upon the predicted impact of the variant. -

Sep 23, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 8 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 30282064) and in one individual affected with sudden cardiac death due to hypertrophic cardiomyopathy (PMID: 34135346). It has also been reported in one asymptomatic individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 2/186304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:3
Sep 11, 2018
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2014
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Gly278GlufsX22 Upon initial review, we considered this variant very likely disease causing, given that there is strong evidence that frameshift variants in MYBPC3 cause cardiomyopathy. This variant has not been reported in published literature (as of 1/27/2012), however it is very likely to cause disease because the deletion of the Guanine nucleotide at position 833 causes a shift in the reading frame, changing the amino acid sequence and creating a premature stop codon. This would be predicted to either lead to a truncated protein or a no protein production due to nonsense-mediate mRNA decay. Both protein truncating and null variants in MYBPC3 have been associated with cardiomyopathy. This variant is not listed in dbSNP or 1000 genomes (as of 1/27/2012). The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~4,700 Caucasian and African American individuals (as of 1/27/2012). However, a missense variant at that same codon is present in 1/3308 Caucasians and 47/1629 African-Americans. Given these data, we think it is likely that this variant causes cardiomyopathy. -

Sep 26, 2023
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 24793961, 27532257, 30282064, 31447099, 33673806, 34135346) -

Hypertrophic cardiomyopathy 4 Pathogenic:3
Oct 13, 2021
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

ACMG codes:PVS1; PS4M; PM2; PP5 -

Oct 12, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 10, 2018
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Cardiomyopathy Pathogenic:2
Mar 08, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 8 of the MYBPC3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 30282064), in an individual affected with sudden cardiac death due to hypertrophic cardiomyopathy (PMID: 34135346), as well as in an asymptomatic individual aged 70 years and older without a history of cardiovascular events (PMID: 34135346). This variant has been identified in 2/186304 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Aug 06, 2020
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Left ventricular noncompaction 10 Pathogenic:1
Oct 12, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Dec 29, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.833delG pathogenic mutation, located in coding exon 8 of the MYBPC3 gene, results from a deletion of one nucleotide at nucleotide position 833, causing a translational frameshift with a predicted alternate stop codon (p.G278Efs*22). This mutation has been reported in an individual with hypertrophic cardiomyopathy (HCM) and in HCM cohorts (Bos JM et al. Mayo Clin. Proc., 2014 Jun;89:727-37; 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503212; hg19: chr11-47369219; API