11-47343135-CAA-CAAA

Position:

• chr11-47343135-CAA-CAAA

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.1236dupT​(p.Glu413fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0290

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 11-47343135-C-CA is Pathogenic according to our data. Variant chr11-47343135-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 237422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1236dupT	p.Glu413fs	frameshift_variant	15/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1236dupT	p.Glu413fs	frameshift_variant	15/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1236dupT	p.Glu413fs	frameshift_variant	14/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1236dupT		non_coding_transcript_exon_variant	15/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2016

This sequence change inserts 1 nucleotide in exon 15 of the MYBPC3 mRNA (c.1236dupT), causing a frameshift at codon 413. This creates a premature translational stop signal (p.Glu413*) and is expected to result in an absent or disrupted protein product. Truncating variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This particular truncation has been reported in the literature in a patient with hypertrophic cardiomyopathy (PMID: 21817903). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 27, 2018

The c.1236dupT variant, located in coding exon 15 of the MYBPC3 gene, results from a duplication of T at nucleotide position 1236, causing a translational frameshift with a predicted alternate stop codon (p.E413*). This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Bortot B et al. Diagn. Mol. Pathol., 2011 Sep;20:175-9). 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)		0.030		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: rs397515894; hg19: chr11-47364686;