NM_000256.3:c.459delC

Variant names:

• chr11-47350059-TG-T
• rs397516052
• NM_000256.3:c.459delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.459delC​(p.Ile154LeufsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,411,996 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.292
• Publications: 10 publications found

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]

MYBPC3 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hypertrophic cardiomyopathy 4

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction 10

  Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• atrial fibrillation

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47350059-TG-T is Pathogenic according to our data. Variant chr11-47350059-TG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000256.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	NM_000256.3	MANE Select	c.459delC	p.Ile154LeufsTer5	frameshift	Exon 4 of 35	NP_000247.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYBPC3	ENST00000545968.6	TSL:5 MANE Select	c.459delC	p.Ile154LeufsTer5	frameshift	Exon 4 of 35	ENSP00000442795.1
	MYBPC3	ENST00000399249.6	TSL:5	c.459delC	p.Ile154LeufsTer5	frameshift	Exon 4 of 34	ENSP00000382193.2
	MYBPC3	ENST00000544791.1	TSL:5	n.459delC		non_coding_transcript_exon	Exon 4 of 27	ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1411996 Hom.: 0 Cov.: 35 AF XY: 0.00000143 AC XY: 1 AN XY: 697766

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 37550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25324

East Asian (EAS) AF: 0.00 AC: 0 AN: 36712

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 80054

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 9.21e-7 AC: 1 AN: 1085988

Other (OTH) AF: 0.00 AC: 0 AN: 58514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Dec 22, 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. p.Ile154LeufsX5 (c.459delC) in MYBPC3 Given the data reviewed below, we consider this variant to be likely disease causing. This variant has been seen in at least 2 presumably unrelated individuals with HCM.. This variant has been reported in one Indian male who was 44 years of age and who had a 24 mm septum (Bashyam et al 2011). In that cohort another patient with HCM had c.456delC as well as a missense variant in MYBPC3, p.Glu710Lys. The authors do not report whether these two variants are cis or trans or any segregation data on either variant. Note in this publication the variant is notated as c.456delC, while GeneDx and HGMD refer to it as c.459delC. Unfortunately Bashyam et al don't include protein nomenclature that might help clarify what they are seeing. I checked with GeneDx about the discrepancy and they noted that the deleted C occurs in a string of Cs. They name the variant assuming the first C is deleted while Bashyam et al seem to notate assuming the last C is deleted (ACCC[C]ATTG vs. A[C]CCCATTTG). Zimmerman et al (2010) list this variant in a supplemental table of pathogenic variants for which genotyping probes were added to their resequencing array for dilated cardiomyopathy. This is a methods paper published by the Laboratory for Molecular Medicine team at Harvard. This suggests that they had reason to suspect this variant was pathogenic (likely unpublished internal data from their clinical genetic testing experience). This is a frame-shifting variant that creates a premature stop codon 5 codons downstream of the variant. The variant is expected to either cause a truncated protein or a completely absent protein due to nonsense-mediated mRNA decay. Many other frameshift and null variants have been identified in MYBPC3 in association with cardiomyopathy (ex. p.Trp792fs, p.Pro794fs, p.Lys1065fs, p.Cys1202fs, p.Pro1208fs, p.Trp1098ter, p.Glu1096ter, p.Cys1124ter, p.Gln1233ter). Furthermore, these types of variants in MYBPC3 are not seen in individuals without cardiomyopathy; there are no frameshift variants listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6000 Caucasian and African American individuals (as of 7/30/2012). In total the variant has not been seen in 6100 published controls and publicly available general population samples, though note that all (or nearly all) of these samples do not match the patient’s ancestry. Bashyam et al report that the variant was absent in 100 presumably healthy controls (ancestry is not noted). GeneDx did not report control data. The variant is not listed in dbSNP or 1000 genomes. Nor is it not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6,000 Caucasian and African American individuals (as of July 2012).

Apr 26, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Expression studies in neonatal rat ventricular cardiomyocytes showed this variant caused significantly reduced levels of a truncated protein and failed to exhibit sarcomere incorporation when compared to wild-type protein (Glazier et al., 2018); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27532257, 23396983, 21959974, 28640247, 25335496, 29875314)

Hypertrophic cardiomyopathy Pathogenic:2

Jan 16, 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.Ile154Leufs*5) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 21959974, 23396983, 25335496). ClinVar contains an entry for this variant (Variation ID: 42755). For these reasons, this variant has been classified as Pathogenic.

Feb 03, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Pathogenic:1

Sep 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397516052; hg19: chr11-47371610;