rs398123279

Positions:

• chr11-47342138-TAC-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.1641_1642delGT​(p.Tyr548fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,674 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.04

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 11-47342138-TAC-T is Pathogenic according to our data. Variant chr11-47342138-TAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 92689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47342138-TAC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.1641_1642delGT	p.Tyr548fs	frameshift_variant	18/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.1641_1642delGT	p.Tyr548fs	frameshift_variant	18/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.1641_1642delGT	p.Tyr548fs	frameshift_variant	17/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.1641_1642delGT		non_coding_transcript_exon_variant	18/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2024	Identified in patients with cardiomyopathy referred for genetic testing at GeneDx and in published literature (PMID: 15519027, 24111713, 33673806); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33673806, 15519027, 24111713, 28971120, 29169752, 37937776, 37652022, 35653365) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2013	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2014	The Tyr548fs variant in MYBPC3 has previously been reported in at least 1 indivi dual with HCM and was absent from 400 control chromosomes (Driest 2004). Data fr om large population studies is insufficient to assess the frequency of this vari ant. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 548 and leads to a premature terminat ion codon 19 amino acids downstream. This alteration is then predicted to lead t o a truncated or absent protein. Heterozygous loss of function of function of th e MYBPC3 gene is an established disease mechanism in HCM. In summary, this varia nt meets our criteria to be classified as pathogenic (http://www.partners.org/pe rsonalizedmedicine/LMM) based upon the predicted impact of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change creates a premature translational stop signal (p.Tyr548Profs*19) 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 individuals with hypertrophic cardiomyopathy (PMID: 15519027, 24111713, 28971120). This variant is also known as E546 fs/19. ClinVar contains an entry for this variant (Variation ID: 92689). For these reasons, this variant has been classified as Pathogenic. -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

deCODE genetics, Amgen

Jul 21, 2023

The variant NM_000256.3:c.1641_1642del (chr11:47342138) in MYBPC3 was detected in 2 heterozygotes out of 58K WGS Icelanders (MAF= 0,002%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PP5) this variant classifies as likely pathogenic. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Oct 09, 2015

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 25, 2018

The c.1641_1642delGT pathogenic mutation, located in coding exon 18 of the MYBPC3 gene, results from a deletion of two nucleotides at nucleotide positions 1641 to 1642, causing a translational frameshift with a predicted alternate stop codon (p.Y548Pfs*19). This variant has been previously reported in several hypertrophic cardiomyopathy cohorts (Van Driest SL et al. J. Am. Coll. Cardiol., 2004 Nov;44:1903-10; Berge KE et al. Clin. Genet., 2014 Oct;86:355-60). In addition to the clinical data 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: rs398123279; hg19: chr11-47363689;