rs727504418
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_000256.3(MYBPC3):c.2671C>T(p.Arg891Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,564,140 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. R891Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.2671C>T | p.Arg891Trp | missense_variant | 26/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.2671C>T | p.Arg891Trp | missense_variant | 26/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.2671C>T | p.Arg891Trp | missense_variant | 25/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.*176C>T | 3_prime_UTR_variant, NMD_transcript_variant | 26/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000263 AC: 5AN: 189998Hom.: 0 AF XY: 0.0000193 AC XY: 2AN XY: 103446
GnomAD4 exome AF: 0.0000198 AC: 28AN: 1411958Hom.: 0 Cov.: 34 AF XY: 0.0000186 AC XY: 13AN XY: 698430
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27532257, 32183154, 31447099, Murakami2014, Maeda2009, 32600061, 25611685) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2023 | - - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 891 of the MYBPC3 protein (p.Arg891Trp). 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 MYBPC3-related conditions (PMID: 25611685, 27532257, 32183154, 32600061). ClinVar contains an entry for this variant (Variation ID: 177949). 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with tryptophan at codon 891 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: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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 | May 15, 2019 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg891Trp variant in MYBPC3 has been reported in 1 individual with DCM (Maeda 2009) and as a de novo occurrence in 1 infant with HCM (Alfares 2015, LMM data). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177949) and has been identified in 3/14552 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg891Trp variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg891Trp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM6, PP3. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 16, 2023 | This missense variant replaces arginine with tryptophan at codon 891 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: 25611685, 27532257, 33495597), in individuals affected with dilated cardiomyopathy (PMID: 27532257, DOI:10.1016/j.fsigss.2009.08.094), and in an individual affected with left ventricular noncompaction cardiomyopathy (PMID: 32183154). This variant has been identified in 6/221382 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. - |
Hypertrophic cardiomyopathy 4;C3715165:Left ventricular noncompaction 10 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 01, 2022 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 15, 2022 | The p.R891W variant (also known as c.2671C>T), located in coding exon 26 of the MYBPC3 gene, results from a C to T substitution at nucleotide position 2671. The arginine at codon 891 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in individuals from cohorts with or referred for genetic testing for dilated cardiomyopathy, hypertrophic cardiomyopathy, and non-compaction cardiomyopathy, and a cohort not selected for the presence of known cardiomyopathy; however details were limited (Maeda K et al. Forensic Sci Int Genetics Suppl Series 2, 2009 499-500, doi:10.1016/j.fsigss.2009.08.094; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 02;19:192-203; Zouk et al. Am J Hum Genet, 2019 09;105:588-605; Hirono K et al. Circ Genom Precis Med, 2020 08;13:e002940; Harper AR et al. Nat Genet, 2021 02;53:135-142). 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