11-47351294-G-T

Position:

• chr11-47351294-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.237C>A​(p.Tyr79*) 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: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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-T is Pathogenic according to our data. Variant chr11-47351294-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 407333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.237C>A	p.Tyr79*	stop_gained	2/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.237C>A	p.Tyr79*	stop_gained	2/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.237C>A	p.Tyr79*	stop_gained	2/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.237C>A		non_coding_transcript_exon_variant	2/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418418 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 700890

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2017

The Y79X (c.237 C>A) variant in the MYBPC3 gene has been reported in at least 3 individuals with confirmedhypertrophic cardiomyopathy (HCM) or who were referred for HCM gene testing (Kapplinger et al., 2014; Bos et al.,2014). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsensemediatedmRNA decay. Other nonsense variants in the MYBPC3 gene, including a different nonsense variant at thesame residue (c.237 C>G), have been reported in Human Gene Mutation Database in association with HCM (Stensonet al., 2014), indicating that loss of function is a known disease mechanism. Finally, the Y79X (c.237 C>A) variantis not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome VariantServer). -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). This particular variant has been reported in the literature in several unrelated individuals with hypertrophic cardiomyopathy (PMID: 23140321, 24510615). This sequence change creates a premature translational stop signal at codon 79 (p.Tyr79*) of the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	14
DANN	Benign	0.96
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.13	N
Vest4		0.89
GERP RS		-6.5

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: rs730880698; hg19: chr11-47372845;