rs730880543
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_000256.3(MYBPC3):c.1471G>A(p.Val491Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000713 in 1,613,870 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. V491A) 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 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1471G>A | p.Val491Met | missense_variant | 17/35 | ENST00000545968.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1471G>A | p.Val491Met | missense_variant | 17/35 | 5 | NM_000256.3 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1471G>A | p.Val491Met | missense_variant | 16/34 | 5 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1471G>A | p.Val491Met | missense_variant, NMD_transcript_variant | 17/27 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000562 AC: 14AN: 249120Hom.: 0 AF XY: 0.0000814 AC XY: 11AN XY: 135152
GnomAD4 exome AF: 0.0000780 AC: 114AN: 1461638Hom.: 0 Cov.: 31 AF XY: 0.0000853 AC XY: 62AN XY: 727114
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152232Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74376
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 02, 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: This variant has been reported in 1 patient with HCM. It is present in gnomAD at a Max MAF of 0.01% (12 European alleles). It is classified in ClinVar with 1 star as Likely Pathogenic by GeneDx (although their blurb suggests VUS) and VUS by Ambry. The variant is not present in Sarcomere Polyphen. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Jan 14, 2022 | This missense variant results in an amino acid substitution of Valine with Methionine at codon 491 of the MYBPC3 gene (transcript: NM_000256.3). This variant has an entry in ClinVar (180940) NM_000256.3(MYBPC3):c.1471G>A (p.Val491Met). This variant occurred in gnomAD with a total MAF of 0 0.0057% and with the highest MAF of 0.0108% in the European population. This position is conserved. In silico functional algorithms predict this variant to be probably damaging (PolyPhen) and deleterious (SIFT). However, no functional studies were performed to confirm either of those predictions. The variant has occurred in the literature in association with hypertrophic cardiomyopathy (HCM) (PMID: 25524337, 20800588). Considering that this is a rare variant and the available evidence is not enough to ascertain its role in disease, it has been classified as Variant of Uncertain Significance. - |
Hypertrophic cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 491 of the MYBPC3 protein (p.Val491Met). This variant is present in population databases (rs730880543, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 20800588, 25351510, 25524337, 33782553; Invitae). ClinVar contains an entry for this variant (Variation ID: 180940). 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. 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 | Aug 23, 2023 | This missense variant replaces valine with methionine at codon 491 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: 20800588, 25351510, 25524337, 27532257, 32841044, 33495597). This variant has also been identified in 14/249120 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 | Dec 30, 2021 | - - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 30, 2023 | This missense variant replaces valine with methionine at codon 491 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: 20800588, 25351510, 25524337, 27532257, 32841044, 33495597). This variant has also been identified in 14/249120 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 | Oct 30, 2018 | The V491M variant of uncertain significance in the MYBPC3 gene has been reported in association with HCM (Coppini et al., 2014; Lopes et al., 2015; Walsh et al., 2017). This variant has been identified in at least two unrelated individuals referred for HCM genetic testing at GeneDx. The V491M variant is observed in 12/111,626 (0.1%) of alleles from individuals of European (non-Finnish) ancestry in large population cohorts (Lek et al., 2016). V491M is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nevertheless, other pathogenic or likely pathogenic variants at a nearby residue (R495G, R495W, R495Q) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), supporting the functional importance of this region of the protein.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2023 | The p.V491M variant (also known as c.1471G>A), located in coding exon 17 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1471. The valine at codon 491 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Millat G et al. Clin Chim Acta, 2010 Dec;411:1983-91; Coppini R et al. J Am Coll Cardiol, 2014 Dec;64:2589-2600; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet Med, 2017 02;19:192-203; Magrì D et al. J Clin Med, 2020 May;9:[ePub ahead of print]). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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