rs372371774
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5
The NM_000256.3(MYBPC3):c.1814A>G(p.Asp605Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000333 in 1,593,244 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D605N) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000035 ( 0 hom. )
Consequence
MYBPC3
NM_000256.3 missense
NM_000256.3 missense
Scores
2
9
9
Clinical Significance
Conservation
PhyloP100: 4.65
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 4 ACMG points.
PM1
?
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000256.3
PM5
?
Other missense variant is known to change same aminoacid residue: Variant chr11-47341222-C-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1814A>G | p.Asp605Gly | missense_variant | 19/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1814A>G | p.Asp605Gly | missense_variant | 19/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1814A>G | p.Asp605Gly | missense_variant | 18/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1814A>G | p.Asp605Gly | missense_variant, NMD_transcript_variant | 19/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152138Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000564 AC: 12AN: 212592Hom.: 0 AF XY: 0.0000522 AC XY: 6AN XY: 114942
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GnomAD4 exome AF: 0.0000347 AC: 50AN: 1441106Hom.: 0 Cov.: 36 AF XY: 0.0000350 AC XY: 25AN XY: 714808
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypertrophic cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | research | Agnes Ginges Centre for Molecular Cardiology, Centenary Institute | Jun 12, 2018 | This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband(s) identified with this variant. For further information please feel free to contact us. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This missense variant replaces aspartic acid with glycine at codon 605 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 20215591, 22337857), in one individual affected with hypertrophic cardiomyopathy (PMID: 25611685), and in one individual suspected of having drug-induced arrhythmia and sudden unexplained death (PMID: 31376648). This variant has been identified in 12/212592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 17, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 605 of the MYBPC3 protein (p.Asp605Gly). This variant is present in population databases (rs372371774, gnomAD 0.01%). This missense change has been observed in individual(s) with familial dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20215591, 33782553). ClinVar contains an entry for this variant (Variation ID: 42573). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 09, 2012 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 19, 2023 | This missense variant replaces aspartic acid with glycine at codon 605 of the MYBPC3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 20215591, 22337857), in one individual affected with hypertrophic cardiomyopathy (PMID: 25611685), and in one individual suspected of having drug-induced arrhythmia and sudden unexplained death (PMID: 31376648). This variant has been identified in 12/212592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 27, 2018 | The D605G variant in the MYBPC3 gene has been reported previously in one individual with dilatedcardiomyopathy (DCM), however information regarding familial segregation was not reported, and in vitro functional studies were not performed (Hershberger et al., 2010). Furthermore, D605G has been reported as variant of uncertain significance by two other clinical laboratories (ClinVar SCV000059088.4; SCV000207044.1; Landrum et al., 2015). The D605G variant was not observed with any significant frequency in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A variant in the same residue (D605N) has been reported in the Human Gene Mutation Database in association with cardiomyopathy, however D605N is classified as a variant of uncertain significance by GeneDx and by another clinical laboratory (Stenson et al., 2014; ClinVar SCV000059087.4; Landrum et al., 2015). D605G results in a non-conservative amino acid substitution at a position where amino acids with similar properties to Aspartic Acid are conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, D605G in the MYBPC3 gene is interpreted as a variant of uncertain significance. - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Aug 20, 2014 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 17, 2022 | The c.1814A>G (p.D605G) alteration is located in exon 19 (coding exon 19) of the MYBPC3 gene. This alteration results from a A to G substitution at nucleotide position 1814, causing the aspartic acid (D) at amino acid position 605 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;D
REVEL
Uncertain
Sift
Benign
T;.;T
Sift4G
Uncertain
D;D;D
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at