11-47337452-G-C

Position:

• chr11-47337452-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.2541C>G​(p.Tyr847*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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-C is Pathogenic according to our data. Variant chr11-47337452-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 42636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47337452-G-C is described in Lovd as [Pathogenic]. Variant chr11-47337452-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.2541C>G	p.Tyr847*	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>G	p.Tyr847*	stop_gained	25/35	5	NM_000256.3	ENSP00000442795.1
MYBPC3	ENST00000399249.6	c.2541C>G	p.Tyr847*	stop_gained	24/34	5		ENSP00000382193.2
MYBPC3	ENST00000544791.1	n.*46C>G		non_coding_transcript_exon_variant	25/27	5		ENSP00000444259.1
MYBPC3	ENST00000544791.1	n.*46C>G		3_prime_UTR_variant	25/27	5		ENSP00000444259.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460940 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726758

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	Not observed at significant frequency 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; A different nucleotide substitution (c.2541 C>A) predicted to result in the same nonsense variant (p.(Y847*)) has also been reported in HGMD in association with hypertrophic cardiomyopathy (HGMD); This variant is associated with the following publications: (PMID: 34598319, 25525159, 24510615, 15519027, 24111713, 21415409, 28450932, 24093860, 29121657, 28193612, 31919335, 33673806, 35626289, 32041989) -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Sep 11, 2018	- -

Hypertrophic cardiomyopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 28, 2020	The c.2541C>A p.Tyr847X variant in MYBPC3 has been reported in 1 individual with hypertrophic cardiomyopathy (HCM; Alfares 2015 PMID: 25611685; Walsh 2017 PMID: 27532257; LMM data) and 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 at this position resulting in the same impact on the protein (c.2541C>G, p.Tyr847X) has been identified in individuals with HCM and is classified as pathogenic by this laboratory as well as others (ClinVar Variation ID 42636). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied: PVS1, PM2, PS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. 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 variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 42636). 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

Mar 09, 2021

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

-

- -

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	Uncertain	0.76	D
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;