Variant 11-47332896-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3408C>A(p.Tyr1136*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,608,768 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.540

Variant links:

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]

MYBPC3 links:

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ACMG classification

Classification made for transcript

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 11-47332896-G-T is Pathogenic according to our data. Variant chr11-47332896-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 36611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332896-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3408C>A	p.Tyr1136*	stop_gained	31/35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3408C>A	p.Tyr1136*	stop_gained	31/35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3408C>A	p.Tyr1136*	stop_gained	30/34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456576

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723998

show subpopulations

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:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	Dec 11, 2019	The MYBPC3 Tyr1136Ter variant has been reported in a compound heterozygous infant born with an ventricular septal defect and LVNC, and a family history of HCM on both sides of the family. The Tyr1136Ter segregated on it's own in the probands mother who had a diagnosis of HCM (Haberer K, et al., 2014). It has also been reported in 4 HCM probands (Alfares AA, et al., 2015; Walsh R, et al., 2017). This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified this variant in a HCM proband and this variant was found to segregate to an affected family member (Ingles et al., 2017). Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) this variant results in loss of function of MYBPC3 (PVS1), is rare in the general population (PM2) and has been reported in at least two HCM probands (PS4_supporting), therefore we classify MYBPC3 Tyr1136Ter as "pathogenic". -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 17, 2023	This sequence change creates a premature translational stop signal (p.Tyr1136*) 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: 24111713, 25262865, 27532257, 28408708). ClinVar contains an entry for this variant (Variation ID: 36611). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 21, 2011	The Tyr1136X variant leads to a premature stop at codon 1136, which is predicted to lead to a truncated or absent protein. Loss of function variants are an esta blished mechanism of disease for the MYBPC3 gene. Therefore, Tyr1136X variant me ets our criteria for pathogenicity (http://pcpgm.partners.org/LMM). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 19, 2023	This variant changes 1 nucleotide in exon 31 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in four unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 24111713, 28408708, 28615295, 33495596) and in an individual suspected to be affected with hypertrophic cardiomyopathy (PMID: 33673806). This variant has also been observed in compound heterozygous state with a known pathogenic MYBPC3 variant in an infant affected with left ventricular non-compaction (PMID: 25262865). Variant Tyr1136* was inherited from the parent who was affected with hypertrophic cardiomyopathy. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MYBPC3 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jun 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2022	Reported in a two-month-old male with LVNC who also harbors the c.2373dupG variant in the MYPBC3 gene; Y1136X was inherited from his mother who has a diagnosis of HCM, and c.2373dupG was inherited from his unaffected father (Haberer et al., 2014); 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; This variant is associated with the following publications: (PMID: 25262865, 24111713, 28408708, 34819141, 33673806, 27532257, 25611685) -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 26, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The p.Y1136* pathogenic mutation (also known as c.3408C>A), located in coding exon 31 of the MYBPC3 gene, results from a C to A substitution at nucleotide position 3408. This changes the amino acid from a tyrosine to a stop codon within coding exon 31. This variant has been detected in hypertrophic cardiomyopathy (HCM) cohorts (Berge KE et al. Clin. Genet., 2014 Oct;86:355-60; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10; Walsh R et al. Genet. Med., 2017 02;19:192-203). This mutation was detected in trans with a second MYBPC3 mutation in an infant with non-compaction cardiomyopathy requiring heart transplant. The mother, who had only the p.Y1136* mutation, had a diagnosis of HCM (Haberer K et al. Can J Cardiol, 2014 Oct;30:1249.e1-3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.91

Vest4

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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