rs397516005

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000256.3(MYBPC3):c.3181C>T(p.Gln1061*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,600,156 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

MYBPC3
NM_000256.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.62

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 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-47333566-G-A is Pathogenic according to our data. Variant chr11-47333566-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 42690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47333566-G-A is described in Lovd as [Pathogenic]. Variant chr11-47333566-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYBPC3	NM_000256.3 link	c.3181C>T	p.Gln1061*	stop_gained	Exon 29 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.3181C>T	p.Gln1061*	stop_gained	Exon 29 of 35	5	NM_000256.3	ENSP00000442795.1		Q14896-1
MYBPC3	ENST00000399249.6 link	c.3181C>T	p.Gln1061*	stop_gained	Exon 28 of 34	5		ENSP00000382193.2		A8MXZ9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152264

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:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000836

AC:

AN:

239364

Hom.:

AF XY:

0.00000766

AC XY:

AN XY:

130586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000819

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1447892

Hom.:

Cov.:

AF XY:

0.00000971

AC XY:

AN XY:

720702

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:

0.000201

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74394

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:

0.000376

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 18, 2013	This mutation is dentoed p.Gln1061Stop (CAG>TAG): c.3181 C>T in exon 29 of the MYBPC3 gene (NM_000256.3). The Gln1061Stop mutation in the MYBPC3 gene has been reported in association with HCM (Jaaskelainen P et al., 2002). Jaaskelainen et al. identified Gln1061Stop in 6 unrelated families with HCM from Finland, and it was not observed in 200 control chromosomes. This study reported this mutation co-segregated with HCM in multiple families and suggested Gln1061Stop may be a founder mutation in the Finnish population. Gln1061Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense mutations in the MYBPC3 gene have been reported in association with HCM. In summary, Gln1061Stop in the MYBPC3 gene is interpreted as a disease-causing mutation. The variant is found in HCM panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hypertrophic cardiomyopathy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 12, 2012	The Gln1061X variant in MYBPC3 has been reported in the literature in six HCM pr obands, segregated in 12 affected or clinically suspicious relatives across five families and was absent from 328 healthy control chromosomes (Jaaskelaine 2002, Poutanen 2006). The families were all of Finnish ancestry, and haplotype analys is suggests that this variant could be a founder mutation in this population (Ja askelaine 2002). In addition, this variant has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (http://evs.gs.washingto n.edu/EVS). Gln1061X is a nonsense variant leading to a premature termination co don at position 1061, which is predicted to lead to a truncated or absent protei n. Heterozygous loss of function of the MYBPC3 gene is an established disease me chanism in HCM patients. In summary, this variant meets our criteria to be class ified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studi es, absence from controls, and established disease mechanism. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2024	This sequence change creates a premature translational stop signal (p.Gln1061*) 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 (rs397516005, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 12110947, 26267065, 27532257). It is commonly reported in individuals of Finnish ancestry (PMID: 22462493). ClinVar contains an entry for this variant (Variation ID: 42690). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	research	Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics	-	- -

Cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 25, 2019	This variant changes 1 nucleotide in exon 29 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 to segregate with hypertrophic cardiomyopathy in several Finnish families (PMID: 12110947) and is thought to be a founder mutation in the Finnish population (PMID: 22462493, 30775854). This variant has also been reported in several unrelated individuals from other ethnic populations affected with hypertrophic cardiomyopathy (PMID: 19666645, 27532257, 18803133). A study has shown this variant changes the morphology, calcium handling, and electrophysiological properties in cardiomyocytes derived from an individual affected with hypertrophic cardiomyopathy (PMID: 27057166). This variant has been identified in 4/270760 chromosomes 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. -

Hypertrophic cardiomyopathy 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 21, 2015

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Dec 08, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2023

The p.Q1061* pathogenic mutation (also known as c.3181C>T), located in coding exon 29 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 3181. This changes the amino acid from a glutamine to a stop codon within coding exon 29. This is the most prevalent mutation reported to cause hypertrophic cardiomyopathy in the Finnish population and has shown a founder effect (Jääskeläinen P et al. J Mol Med (Berl). 2002;80(7):412-22; Jääskeläinen P et al. Ann Med. 2013;45(1):85-90). 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. -

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

0.99

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

Vest4

0.82

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.88

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.88

Position offset: 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

Other links and lift over