rs727503190
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_000256.3(MYBPC3):c.2234A>G(p.Asp745Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
MYBPC3
NM_000256.3 missense
NM_000256.3 missense
Scores
14
5
1
Clinical Significance
Conservation
PhyloP100: 7.67
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 Uncertain_significance. Variant got 5 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000256.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2234A>G | p.Asp745Gly | missense_variant | 23/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2234A>G | p.Asp745Gly | missense_variant | 23/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2234A>G | p.Asp745Gly | missense_variant | 22/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.2234A>G | p.Asp745Gly | missense_variant, NMD_transcript_variant | 23/27 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, no assertion criteria provided | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Feb 20, 2020 | The MYBPC3 Asp745Gly variant is absent from the he Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified the MYBPC3 Asp745Gly variant in an HCM proband where one additional MYBPC3 (Pro873His) variant of uncertain significance has also been observed (Ingles J., et al 2005). Recently we also identified a third variant (CSRP3 Arg146Cys) of "uncertain significance". Both MYBPC3 variants were found to segregate to an affected first degree family member. In silico tools (SIFT, PolyPhen-2, MutationTaster) support a deleterious role but is not sufficient enough to determine pathogenicity. We cannot rule out its possible role in disease but due to limited evidence, we class this variant as one of "uncertain significance". - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 02, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects MYBPC3 function (PMID: 26688216). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 30142). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16199542, 21839045, 27532257, 28679633, 30984009, 33782553). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 745 of the MYBPC3 protein (p.Asp745Gly). - |
Hypertrophic cardiomyopathy 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 2007 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 20, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 04, 2022 | The p.Asp745Gly variant in MYBPC3 has been reported in 4 individuals with hypertrophic cardiomyopathy (Ingles 2005 PMID: 16199542, Maron 2012 PMID: 21839045, Kresin 2019 PMID: 30984009, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 39098) and was absent from large population studies. In vitro functional studies provide some evidence that this variant impacts protein function, as this variant showed increased action potential in heart tissue from an HCM patient in 1 study, and displayed interference in protein folding in another (Nadvi 2016 PMID: 26688216, Flenner 2021 PMID: 33957110). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PS4_Supporting, PP3. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at