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rs121909374

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_000256.3(MYBPC3):c.1624G>T(p.Glu542Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

MYBPC3
NM_000256.3 stop_gained, splice_region

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 5.67
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 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;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 11-47342578-C-A is Pathogenic according to our data. Variant chr11-47342578-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 430571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MYBPC3NM_000256.3 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 17/35 ENST00000545968.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MYBPC3ENST00000545968.6 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 17/355 NM_000256.3 P4Q14896-1
MYBPC3ENST00000399249.6 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant 16/345 A2
MYBPC3ENST00000544791.1 linkuse as main transcriptc.1624G>T p.Glu542Ter stop_gained, splice_region_variant, NMD_transcript_variant 17/275

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxSep 11, 2018The E542X variant in the MYBPC3 gene has been reported previously in a cohort of HCM patients, however, no specific clinical details were provided (Lopes et al., 2015). E542X 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 Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Moreover, the E542X variant is not observed in large population cohorts (Lek et al., 2016). Finally, this variant was identified independently in a patient with HCM referred for genetic testing at GeneDx.In summary, E542X in the MYBPC3 gene is interpreted as a pathogenic variant. -
Hypertrophic cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJul 18, 2021This sequence change creates a premature translational stop signal (p.Glu542*) 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). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 430571). This premature translational stop signal has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25351510). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
Cadd
Pathogenic
47
Dann
Uncertain
1.0
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.95
GERP RS
4.6

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
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: rs121909374; hg19: chr11-47364129; API