11-47351294-G-C

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.237C>G(p.Tyr79Ter) variant causes a stop gained 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. Y79Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.32

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 11-47351294-G-C is Pathogenic according to our data. Variant chr11-47351294-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 181132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47351294-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3	c.237C>G	p.Tyr79Ter	stop_gained	2/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6	c.237C>G	p.Tyr79Ter	stop_gained	2/35	5	NM_000256.3	P4
MYBPC3	ENST00000399249.6	c.237C>G	p.Tyr79Ter	stop_gained	2/34	5		A2
MYBPC3	ENST00000544791.1	c.237C>G	p.Tyr79Ter	stop_gained, NMD_transcript_variant	2/27	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This variant changes 1 nucleotide in exon 2 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than five unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 17394878, 20624503, 20800588, 21896538, 24111713, 28138913, 28640247, 28971120, 32841044, 17394878, 21896538, 28138913). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 17394878, 21896538, 28138913). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants causing the same premature translation stop signal (c.237C>A p.Tyr79X and c.236dupA p.Tyr79X), are also known to be disease-causing (ClinVar variation ID: 407333 and 372710). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2015	The p.Tyr79X variant in MYBPC3 has been reported in 1 Caucasian individual with HCM, segregated with disease in 3 affected relatives (including 1 obligate carri er), and was absent from 200 ethnically matched controls (Garcia-Pavia 2007, Gar cia-Pavia 2011). It has also been detected by another clinical testing laborato ry and is noted in the ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/var iation/181132). Data from large population studies is insufficient to assess the frequency of this variant. This nonsense variant leads to a premature terminati on codon at position 79, which is predicted to lead to a truncated or absent pro tein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in individuals with HCM. In summary, this variant meets our criteria to be classified as pathogenic for HCM in an autosomal dominant manner (http://w ww.partners.org/personalizedmedicine/LMM) based on the predicted impact of the v ariant. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2019

Not observed in large population cohorts (Lek et al., 2016); Nonsense 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: 25525159, 17394878, 24111713, 21896538, 28971120, 20624503, 28640247) -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

Sep 01, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000181132 / PMID: 17394878). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	14
Dann	Benign	0.97
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.15	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.89
GERP RS		-6.5

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: rs730880698; hg19: chr11-47372845;