rs730880719

chr11-47333196-TG-T

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.3327del(p.Met1110TrpfsTer79) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T1109T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.35

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 11-47333196-TG-T is Pathogenic according to our data. Variant chr11-47333196-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 181155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.3327del	p.Met1110TrpfsTer79	frameshift_variant	30/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.3327del	p.Met1110TrpfsTer79	frameshift_variant	30/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.3327del	p.Met1110TrpfsTer79	frameshift_variant	29/34	5		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 20, 2011

A deletion of a single “C” nucleotide in exon 30 of the MYBPC3 gene. The normal sequence with the base that is deleted in braces is: AGAC{C}ATGG. This mutation is denoted c.3327delC at the cDNA level or p.Met1110TrpfsX79 at the protein level. The c.3327delC mutation in the MYBPC3 gene causes a shift in reading frame at codon Methionine 1110, changing it to a Tryptophan, and creates a premature Stop codon at position 79 of the new reading frame. Although this mutation has not been reported previously to our knowledge, it is expected to result in an abnormal, truncated protein or in absence of protein from this allele due to mRNA decay, and therefore is interpreted to be a disease-causing mutation.The variant is found in HCM panel(s). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 18, 2016

- -

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: rs730880719; hg19: chr11-47354747;