rs727504349

Positions:

• chr11-47335200-C-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.2747G>A​(p.Trp916Ter) variant causes a stop gained change. 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: 33)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.72

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 11-47335200-C-T is Pathogenic according to our data. Variant chr11-47335200-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 177835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47335200-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2747G>A	p.Trp916Ter	stop_gained	27/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.2747G>A	p.Trp916Ter	stop_gained	27/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.2747G>A	p.Trp916Ter	stop_gained	26/34	5		ENSP00000382193	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 14, 2014	The p.Trp916X variant in MYBPC3 has been identified by our laboratory in 1 Cauca sian individual with HCM and segregated with disease in 4 affected relatives (in cluding 2 obligate carriers). Data from large population studies are insufficien t to assess the frequency of this variant. This nonsense variant leads to a prem ature termination codon at position 916, which is predicted to lead to a truncat ed or absent protein. Heterozygous loss-of-function of the MYBPC3 gene is an est ablished disease mechanism in individuals with HCM. In summary, this variant mee ts our criteria to be classified as pathogenic for HCM in an autosomal dominant manner based upon the predicted impact to the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 07, 2023	This sequence change creates a premature translational stop signal (p.Trp916*) 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: 25611685, 27532257, 29030401). ClinVar contains an entry for this variant (Variation ID: 177835). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2023

Identified in individuals with HCM referred for genetic testing at GeneDx and at least one individual with HCM in published literature, and shown to segregate with disease in four affected relatives in addition to the proband by another clinical laboratory (Alfares et al., 2015; Walsh et al., 2017; Cirino et al., 2017; Christensen et al., 2018; ClinVar SCV000204139.4; 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: 27532257, 29565423, 29030401, 25611685) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2022

The p.W916* pathogenic mutation (also known as c.2747G>A), located in coding exon 27 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 2747. This changes the amino acid from a tryptophan to a stop codon within coding exon 27. This variant has been detected in individuals from hypertrophic cardiomyopathy cohorts (Walsh R et al. Genet Med, 2017 02;19:192-203; Christensen KD et al. Genet Med, 2018 12;20:1544-1553). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented 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

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.89
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs727504349; hg19: chr11-47356751;