rs776734314
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM5PP3
The NM_000256.3(MYBPC3):c.1409G>A(p.Arg470Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,118 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1409G>A | p.Arg470Gln | missense_variant | 16/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1409G>A | p.Arg470Gln | missense_variant | 16/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1409G>A | p.Arg470Gln | missense_variant | 15/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1409G>A | p.Arg470Gln | missense_variant, NMD_transcript_variant | 16/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 247146Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134160
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1460758Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726560
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152360Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74496
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 470 of the MYBPC3 protein (p.Arg470Gln). This variant is present in population databases (rs776734314, gnomAD 0.003%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 27483260, 27600940, 29398688; Invitae). ClinVar contains an entry for this variant (Variation ID: 403203). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg470 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23233322, 33782553). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2023 | This missense variant replaces arginine with glutamine at codon 470 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27483260, 27600940, 29398688, 33495597) and in an individual affected with aortic dissection (PMID: 30959811). This variant has been identified in 1/247146 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 specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2024 | Variant summary: MYBPC3 c.1409G>A (p.Arg470Gln) results in a conservative amino acid change in Immunoglobulin subtype 2 domain (IPR003598) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247146 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1409G>A has been reported in the literature in several individuals affected with HCM or undertaking Cardiomyopathy panel testing (Harris_2011, Teramoto_2018, Emrahi_2022). In a large cross-sectional study with individuals referred for diagnostic sequencing for HCM and DCM, this variant was evaluated as a VUS change with penetrance of 0.017 (McGurk_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21415409, 37652022, 29398688, Emrahi et al). ClinVar contains an entry for this variant (Variation ID: 403203). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 31, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD; ExAC: 1/11104 Latino; - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 23, 2023 | This missense variant replaces arginine with glutamine at codon 470 of the MYBPC3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 27483260, 27600940, 29398688, 33495597) and in an individual affected with aortic dissection (PMID: 30959811). This variant has been identified in 1/247146 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 | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 11, 2015 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2019 | Reported in association with HCM (Rubattu et al., 2016; Cecconi et al., 2016; Teramoto et al., 2018); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID# 403203; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27483260, 25320358, 28679633, 27600940, 21415409, 29398688) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 07, 2022 | The p.R470Q variant (also known as c.1409G>A), located in coding exon 16 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1409. The arginine at codon 470 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts, as well as a sudden unexplained death cohort (Cecconi M et al. Int J Mol Med, 2016 Oct;38:1111-24; Teramoto R et al. Circ J, 2018 03;82:1139-1148; Hata Y et al. J Clin Med, 2019 Apr;8:[ePub ahead of print]). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at