rs727504234
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000256.3(MYBPC3):c.844C>T(p.Arg282Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,573,802 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.844C>T | p.Arg282Trp | missense_variant | 8/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.844C>T | p.Arg282Trp | missense_variant | 8/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.844C>T | p.Arg282Trp | missense_variant | 8/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.844C>T | p.Arg282Trp | missense_variant, NMD_transcript_variant | 8/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152038Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000107 AC: 2AN: 186750Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 100488
GnomAD4 exome AF: 0.0000274 AC: 39AN: 1421764Hom.: 0 Cov.: 33 AF XY: 0.0000284 AC XY: 20AN XY: 703528
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74264
ClinVar
Submissions by phenotype
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 24, 2023 | This missense variant replaces arginine with tryptophan at codon 282 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). In vitro experimental functional assays have shown that this variant may cause reduced phosphorylation of the MYBPC3 protein (PMID: 35227736; DOI:10.1096/fasebj.30.1_supplement.1012.3). However, clinical significance of these observations is not known. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 11499719, 12974739, 27532257). In one family, this variant segregated with disease in several affected individuals (PMID: 11499719). This variant has been identified in 5/218036 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 | May 06, 2020 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 29, 2023 | 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 disrupt the consensus splice site. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 282 of the MYBPC3 protein (p.Arg282Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11499719, 27532257). ClinVar contains an entry for this variant (Variation ID: 177621). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces arginine with tryptophan at codon 282 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. An experimental functional assay has shown that this variant may cause reduced phosphorylation of the MYBPC3 protein (Giuffre et al., 2016). However, clinical significance of this observation is not known. This variant has been reported in three related individuals affected with hypertrophic cardiomyopathy (PMID: 11499719) and in an unrelated individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 5/218036 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:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 12, 2019 | The p.Arg282Trp variant in MYBPC3 has been reported in 3 individuals with HCM, one of whom also carried a likely pathogenic variant in MYH7, and segregated with disease in 3 affected relatives, including 1 obligate carrier (Erdmann 2001, Erdmann 2003, Walsh 2017, LMM data). It has been identified in 0.015% (3/20520) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and reported in ClinVar (Variation ID #177621). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS4_Supporting, PP1, BP4. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2021 | Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#177621; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 12974739, 11499719, 25525159) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2023 | The p.R282W variant (also known as c.844C>T), located in coding exon 8 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 844. The arginine at codon 282 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in a proband with hypertrophic cardiomyopathy (HCM) as well as in affected and unaffected relatives (Erdmann J et al. J Am Coll Cardiol, 2001 Aug;38:322-30; Erdmann J et al. Clin Genet, 2003 Oct;64:339-49). This variant has also been detected in individuals who underwent genet testing for HCM (Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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