chr11-47336003-T-TG

Variant names:

• chr11-47336003-T-TG
• rs397515979
• NM_000256.3:c.2610dupC

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.2610dupC​(p.Ser871GlnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,366,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.292
• Publications: 5 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 11-47336003-T-TG is Pathogenic according to our data. Variant chr11-47336003-T-TG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 42646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2610dupC	p.Ser871GlnfsTer13	frameshift_variant	Exon 26 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2610dupC	p.Ser871GlnfsTer13	frameshift_variant	Exon 26 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2610dupC	p.Ser871GlnfsTer13	frameshift_variant	Exon 25 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*115dupC		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*115dupC		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1366568 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 670944

⚠️ 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: 30182

American (AMR) AF: 0.00 AC: 0 AN: 34470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21492

East Asian (EAS) AF: 0.00 AC: 0 AN: 36160

South Asian (SAS) AF: 0.00 AC: 0 AN: 70694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3802

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1063338

Other (OTH) AF: 0.0000178 AC: 1 AN: 56180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Feb 23, 2024

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.Ser871Glnfs*13) 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, dilated cardiomyopathy (PMID: 25132132, 36252119). ClinVar contains an entry for this variant (Variation ID: 42646). For these reasons, this variant has been classified as Pathogenic. -

Aug 08, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiomyopathy Pathogenic:1

Jan 13, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 26 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 individuals affected with hypertrophic cardiomyopathy (PMID: 25132132, 25611685, 27532257, 30847666, 33495596, 33495597). It has also been reported in an infant affected with dilated cardiomyopathy who also carried an additional pathogenic truncation variant in the same gene (PMID: 36252119). This variant has not been identified 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:1

May 16, 2012

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2610dupC mutation in the MYBPC3 gene has not been reported previously in association with HCM or as a benign polymorphism to our knowledge. The c.2610dupC variant causes a shift in reading frame beginning with Serine codon 871, changing it to a Leucine, and creates a premature stop codon at position 13 of the new reading frame. This variant is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Other frameshift variants in the MYBPC3 gene have been reported in association with HCM. In summary, c.2610dupC in the MYBPC3 gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515979; hg19: chr11-47357554; COSMIC: COSV99920204;