Variant 11-47332244-C-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.3642G>A(p.Trp1214Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,680 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.56

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:

Genome browser will be placed here

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 11-47332244-C-T is Pathogenic according to our data. Variant chr11-47332244-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47332244-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYBPC3	NM_000256.3 linkuse as main transcript	c.3642G>A	p.Trp1214Ter	stop_gained	33/35	ENST00000545968.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYBPC3	ENST00000545968.6 linkuse as main transcript	c.3642G>A	p.Trp1214Ter	stop_gained	33/35	5	NM_000256.3	P4	Q14896-1
MYBPC3	ENST00000399249.6 linkuse as main transcript	c.3642G>A	p.Trp1214Ter	stop_gained	32/34	5		A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152220

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:

6.84e-7

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727036

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

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

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2017	The W1214X variant in the MYBPC3 gene has been reported in an Indian male patient with familial HCM who also harbored another variant in the MYH7 gene (Bashyam M et al., 2012). The variant was absent from 100 ethnically matched control individuals. W1214X is predicted to cause loss of normal protein function either by protein truncation or nonsense mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in association with HCM. In summary, W1214X in the MYBPC3 gene is interpreted as a disease-causing variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYBPC3: PVS1, PM2, PS4:Moderate -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change creates a premature translational stop signal (p.Trp1214*) 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 present in population databases (rs368765949, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 21959974, 24093860). ClinVar contains an entry for this variant (Variation ID: 162506). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 16, 2021

- -

Cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Aug 20, 2019

This variant changes 1 nucleotide in exon 33 of the MYBPC3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. A different variant (c.3641G>A) resulting in the same protein effect (p.Trp1214*) has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 21959974, 24093860). 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. Based on the available evidence, this variant is classified as Pathogenic. -

Primary dilated cardiomyopathy;C4021133:Left ventricular noncompaction cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Oct 15, 2020

We observed a c.3642G>A (p.W1214*) genetic variant in a 30-y.o. female proband, diagnosed with non-compaction cardiomyopathy, dilatation of cardiac chambers and heart rhythm disturbances. The proband also carried the additional variant of unknown clinical significance in MYBPC3 gene - p.P186L in heterozygous state. The family was unavailable for screening. The p.W1214* genetic variant is a nonsense mutation in the MYBPC3 gene. No functional studies are available for the p.W1214* variant, however, nonsense variants in MYBPC3 gene are well-known to cause cardiomyopathy through haploinsufficiency. According to Cardio Classifier predictions, mRNA carrying the p.W1214* variant, will be processed through nonsence-mediated decay mechanism, leading to haploinsufficiency. We assume that the p.W1214* variant could be classified as likely pathogenic. -

Hypertrophic cardiomyopathy 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Genetics and Molecular Cardiology, University of São Paulo

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 02, 2020

The p.W1214* pathogenic mutation (also known as c.3642G>A), located in coding exon 33 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 3642. This changes the amino acid from a tryptophan to a stop codon within coding exon 33. This mutation has been reported in hypertrophic cardiomyopathy (HCM) cohorts, including one HCM case with an additional MYH7 variant also detected (Bashyam MD et al. Mol. Cell. Biochem., 2012 Jan;360:373-82; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Kapplinger JD et al. J Cardiovasc Transl Res, 2014 Apr;7:347-61; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:[Epub ahead of print]). This variant has also been seen in an exome cohort, but cardiovascular history was not provided (Andreasen C et al. Eur. J. Hum. Genet., 2013 Sep;21:918-28; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). 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. -

MYBPC3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 11, 2024

The MYBPC3 c.3642G>A variant is predicted to result in premature protein termination (p.Trp1214*). This variant has been reported in individuals with autosomal dominant hypertrophic cardiomyopathy (Marsiglia et al. 2013. PubMed ID: 24093860; Table S1 in Helms et al. 2020. PubMed ID: 32841044; Table S2 in Burstein et al. 2021. PubMed ID: 32746448). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MYBPC3 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.97

MutationTaster

Benign

1.0

A;A;A

Vest4

0.90

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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