11-47337452-G-T

Position:

• chr11-47337452-G-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.2541C>A​(p.Tyr847Ter) 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0690

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 11-47337452-G-T is Pathogenic according to our data. Variant chr11-47337452-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 177852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337452-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2541C>A	p.Tyr847Ter	stop_gained	25/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2541C>A	p.Tyr847Ter	stop_gained	25/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2541C>A	p.Tyr847Ter	stop_gained	24/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.*46C>A		3_prime_UTR_variant, NMD_transcript_variant	25/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 11, 2020	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This nonsense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 15519027, 25611685, 29121657). ClinVar contains an entry for this variant (Variation ID: 177852). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr847*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2021	The p.Tyr847X variant in MYBPC3 has been reported in 1 individual with hypertrophic cardiomyopathy (Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM data). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 847, which is predicted to lead to a truncated or absent protein. Loss of function of the MYBPC3 gene is an established disease mechanism in autosomal dominant HCM. Another variant involving this codon (c.2541C>G, p.Tyr847X) has been identified in individuals with hypertrophic cardiomyopathy and is classified as pathogenic by this and other laboratories. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM5. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.96
GERP RS		1.5

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: rs397515974; hg19: chr11-47359003; COSMIC: COSV99921105;