11-47346298-G-C

Position:

• chr11-47346298-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.999C>G​(p.Tyr333Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y333Y) 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:5
• Conservation: PhyloP100: -0.704

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 11-47346298-G-C is Pathogenic according to our data. Variant chr11-47346298-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 177706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47346298-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.999C>G	p.Tyr333Ter	stop_gained	12/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.999C>G	p.Tyr333Ter	stop_gained	12/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.999C>G	p.Tyr333Ter	stop_gained	11/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.999C>G	p.Tyr333Ter	stop_gained, NMD_transcript_variant	12/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2015	The p.Tyr333X variant in MYBPC3 has been reported in 3 individuals with HCM, seg regated with disease in 1 affected relative from 1 family (Kassem 2013, LMM unpu blished data) and was absent from large population studies. This nonsense varian t leads to a premature termination codon at position 333, which is predicted to lead to a truncated protein. Heterozygous loss of function of the MYBPC3 gene is an established disease mechanism in HCM. In summary, this variant meets our cri teria to be classified as pathogenic for HCM in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change creates a premature translational stop signal (p.Tyr333*) 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 individual(s) with hypertrophic cardiomyopathy (PMID: 23233322, 25351510, 25611685). ClinVar contains an entry for this variant (Variation ID: 177706). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Oct 28, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2023

Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 177706; ClinVar); Not observed in large population cohorts (gnomAD); 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: 31006259, 25611685, 27532257) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2013

The p.Y333X pathogenic mutation, located in coding exon 12 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 999. This changes the amino acid from a tyrposine to a stop codon within coding exon 12. This alteration was identifed in 1 of 192 unrelated Egyptians with a clinical diagnosis of hypertrophic cardiomyopathy (Kassem Hsh etal. J Cardiovasc Transl Res. 2013;6:65-80). Futhermore, haploinsufficiency of MYBPC3 has been indicated as a mechanism of disease, causing hypertrophic cardiomyopathy (Marston et al. 2012 J Muscle Res Cell Motil 33:75-80). In addition to the data presented in the literature, premature stop codons are typically deleterious in nature and interpreted as disease-causing mutations (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). Based on the supporting evidence, p.Y333X is interpreted as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.74
GERP RS		-5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs367947846; hg19: chr11-47367849;