rs397516005

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

5
1
1

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]

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
MYBPC3NM_000256.3 linkc.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
MYBPC3ENST00000545968.6 linkc.3181C>T p.Gln1061* stop_gained Exon 29 of 35 5 NM_000256.3 ENSP00000442795.1 Q14896-1
MYBPC3ENST00000399249.6 linkc.3181C>T p.Gln1061* stop_gained Exon 28 of 34 5 ENSP00000382193.2 A8MXZ9

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152264
Hom.:
0
Cov.:
33
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:
2
AN:
239364
Hom.:
0
AF XY:
0.00000766
AC XY:
1
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:
9
AN:
1447892
Hom.:
0
Cov.:
32
AF XY:
0.00000971
AC XY:
7
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:
4
AN:
152264
Hom.:
0
Cov.:
33
AF XY:
0.0000403
AC XY:
3
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:
2

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:3
-
Clinical Genetics, Academic Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 18, 2013
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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). -

May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Pathogenic:3
Jul 12, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Dec 04, 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.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. -

-
Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Cardiomyopathy Pathogenic:2
May 10, 2018
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 25, 2019
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Sep 21, 2015
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy Pathogenic:1
Dec 08, 2015
Blueprint Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Sep 08, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
D
BayesDel_noAF
Pathogenic
0.63
CADD
Pathogenic
50
DANN
Uncertain
1.0
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
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.

Other links and lift over

dbSNP: rs397516005; hg19: chr11-47355117; API