rs397515970

Positions:

• chr11-47337468-T-TA

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.2524_2525insT​(p.Tyr842LeufsTer42) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y842Y) 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:3
• Conservation: PhyloP100: 8.95

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 11-47337468-T-TA is Pathogenic according to our data. Variant chr11-47337468-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 42632.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.2524_2525insT	p.Tyr842LeufsTer42	frameshift_variant	25/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2524_2525insT	p.Tyr842LeufsTer42	frameshift_variant	25/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.2524_2525insT	p.Tyr842LeufsTer42	frameshift_variant	24/34	5		A2
MYBPC3	ENST00000544791.1	c.*29_*30insT		3_prime_UTR_variant, NMD_transcript_variant	25/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 14, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 42632). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 23396983, 27532257, 28615295). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr842Leufs*42) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 26, 2011	The Tyr842fs variant has not been reported in the literature nor been previously detected in over 1,600 Caucasian probands tested by our laboratory. This varia nt meets our criteria for pathogenicity (http://pcpgm.partners.org/LMM) based on the following data. This individual?s racial background is reported to be Cauca sian and the low frequency of this variant in this population supports a pathoge nic role. In addition, the variant is predicted to cause a frameshift, which al ters the protein's amino acid sequence beginning at codon 842 and leads to a pre mature stop codon 42 amino acids downstream. This alteration is then predicted t o lead to a truncated or absent protein (loss of function). Loss of function of the MYBPC3 gene is an established disease mechanism for HCM, which strongly supp orts a pathogenic role of the Tyr842fs variant. -

Hypertrophic cardiomyopathy 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

May 30, 2015

The MYBPC3 Tyr842fs variant is absent from the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 1 HCM proband (IVS 24mm). This MYBPC3 insertion variant (c.2525dupT) is predicted to interrupt the reading frame and lead to a premature stop codon, and a truncated or absent protein. Loss-of-function mutations in the MYBPC3 gene are an established mechanism of disease in HCM hence, we classify MYBPC3 Tyr842fs as "pathogenic". -

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: rs397515970; hg19: chr11-47359019;