11-47342928-AGG-AGGG

Variant names:

• chr11-47342928-A-AG
• rs727503203
• NM_000256.3:c.1358dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.1358dupC​(p.Val454CysfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.51

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 11-47342928-A-AG is Pathogenic according to our data. Variant chr11-47342928-A-AG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181147.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.1358dupC	p.Val454CysfsTer21	frameshift_variant	Exon 16 of 35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1358dupC	p.Val454CysfsTer21	frameshift_variant	Exon 16 of 35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1358dupC	p.Val454CysfsTer21	frameshift_variant	Exon 15 of 34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1358dupC		non_coding_transcript_exon_variant	Exon 16 of 27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy 4 Pathogenic:2

-

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 27, 2020

Clinical Genetics Laboratory, Region Ostergotland

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2, PP5 -

Cardiomyopathy Pathogenic:1

Dec 07, 2011

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An insertion of a single “C” nucleotide in exon 16 of the MYBPC3 gene. The normal sequence with the base that is inserted in braces is: GCCCCC{C}TGTGC. This mutation is denoted c.1358dupC at the cDNA level or p.Val454CysfsX21 at the protein level. Although the c.1358dupC mutation in the MYBPC3 gene has not been reported previously, this mutation causes a shift in reading frame starting at codon Valine 454, changing it to a Cysteine, and creates a premature stop codon at position 21 of the new reading frame. The c.1358dupC mutation is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay. Multiple frameshift mutations in the MYBPC3 gene have been reported in association with HCM The variant is found in HCM panel(s). -

Cardiovascular phenotype Pathogenic:1

Jan 02, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1358dupC pathogenic mutation, located in coding exon 16 of the MYBPC3 gene, results from a duplication of C at nucleotide position 1358, causing a translational frameshift with a predicted alternate stop codon (p.V454Cfs*21). This variant was reported in individual(s) with features consistent with hypertrophic cardiomyopathy (HCM) (Singh SR et al. Circ Heart Fail, 2017 Oct;10:[ePub ahead of print]; Jääskeläinen P et al. ESC Heart Fail, 2019 Apr;6:436-445; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

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

Other links and lift over

dbSNP: rs727503203; hg19: chr11-47364479;