rs397515992

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000256.3(MYBPC3):c.2905C>T(p.Gln969*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000217 in 1,381,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 stop_gained, splice_region

Scores

Splicing: ADA: 0.2223

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:19

Conservation

PhyloP100: 3.76

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
hypertrophic cardiomyopathy 4
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
left ventricular noncompaction 10
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, LIMITED Submitted by: Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
arrhythmogenic right ventricular cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
atrial fibrillation
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MYBPC3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 11-47335042-G-A is Pathogenic according to our data. Variant chr11-47335042-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 42669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 27 of 35	ENST00000545968.6	NP_000247.2	Q14896-1A5YM48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6 link	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 27 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.2905C>T	p.Gln969*	stop_gained, splice_region_variant	Exon 26 of 34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000217

AC:

AN:

1381244

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

677732

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31174

American (AMR)

AF:

0.00

AC:

AN:

38098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22188

East Asian (EAS)

AF:

0.00

AC:

AN:

37056

South Asian (SAS)

AF:

0.00

AC:

AN:

73876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1065620

Other (OTH)

AF:

0.00

AC:

AN:

56894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Jun 22, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in several patients referred for HCM genetic testing at GeneDx and found to segregate with disease in a relative of one proband; Reported in one patient with DCM (Hazebroek et al., 2015); 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: 25525159, 26914223, 20359594, 22267749, 27373729, 9541104, 27532257, 15519027, 18533079, 21302287, 24111713, 26383716, 29540472, 30282064, 31006259, 29398688, 34137518, 24704860, 9541100, 33673806, 32880476, 32746448, 36203036, 34076677, 35653365) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYBPC3: PVS1, PM2 -

Jul 19, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 04, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy

Pathogenic:6

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Nov 18, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The Gln969X variant has been reported in the literature in at least 2 individual s with clinical features of HCM (Yu 1998, Van Driest 2004) and in our laboratory in three other individuals with HCM. The Gln969X variant leads to a premature s top at codon 969. This alteration is predicted to lead to a truncated or absent protein. Loss of function variants are an established mechanism of disease for t he MYBPC3 gene. It should be noted that this variant was seen in one family alo ng with a second likely pathogenic variant, suggesting that this variant may hav e a milder effect. In summary, the Gln969X variant is highly likely to be patho genic. -

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln969*) 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 individuals with hypertrophic cardiomyopathy (PMID: 9541104, 27532257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 42669). For these reasons, this variant has been classified as Pathogenic. -

Genetics and Genomics Program, Sidra Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes one nucleotide in exon 27 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 over 10 individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 33673806, 34137518, 35653365, 36203036) and in a large family affected with familial hypertrophic cardiomyopathy (PMID: 9541104). 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. -

Nov 20, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This heterozygous nonsense variant in the MYBPC3 gene was identified in a male patient (53 years old) with familial hypertrophic cardiomyopathy -

Hypertrophic cardiomyopathy 4

Pathogenic:3

May 26, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 09, 2020

Clinical Genetics Laboratory, Region Ostergotland

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4, PM2, PP5 -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiomyopathy

Pathogenic:2

Mar 22, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10

Pathogenic:1

Nov 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypertrophic cardiomyopathy 1

Pathogenic:1

Jul 21, 2015

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The MYBPC3 Gln969* variant has been observed in multiple unrelated HCM cases (Roncarati R, et al., 2011; Van Driest SL, et al., 2004; Yu B, et al., 1998) and absent in >150 controls (Van Driest SL, et al., 2004; Roncarati R, et al., 2011). Furthermore, this variant is absent from both the 1000 genomes project (http://www.1000genomes.org/) and Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified the MYBPC3 Gln969* variant in an HCM family where two additional variants in MYBPC3 (Arg668His; "uncertain significance") and MYH7 (Arg1079Gln; "uncertain significance") have also been observed in the family (Girolami F, et al., 2010). MYPBC3 Gln969* was identified in our HCM proband who carried the additional MYH7 Arg1079Gln variant. The proband's affected sister carries this MYBPC3 Gln969* as well as both additional MYBPC3 and MYH7 variants variants (Girolami F, et al., 2010). This MYBPC3 variant results in a premature stop codon in place of glutamine (Gln) at position 969 and predicted to result in a truncated protein. Given that loss-of-function variants in MYBPC3 are an established mechanism of disease in HCM, and that MYBPC3 Gln969* has been observed in other cases of familial HCM, we classify this variant as "pathogenic". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.8

Vest4

0.97

GERP RS

3.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.22

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over