rs397515923
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate
The NM_000256.3(MYBPC3):c.1766G>A(p.Arg589His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000038 in 1,579,488 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. R589G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYBPC3 | NM_000256.3 | c.1766G>A | p.Arg589His | missense_variant | 18/35 | ENST00000545968.6 | NP_000247.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MYBPC3 | ENST00000545968.6 | c.1766G>A | p.Arg589His | missense_variant | 18/35 | 5 | NM_000256.3 | ENSP00000442795 | P4 | |
MYBPC3 | ENST00000399249.6 | c.1766G>A | p.Arg589His | missense_variant | 17/34 | 5 | ENSP00000382193 | A2 | ||
MYBPC3 | ENST00000544791.1 | c.1766G>A | p.Arg589His | missense_variant, NMD_transcript_variant | 18/27 | 5 | ENSP00000444259 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000102 AC: 2AN: 196408Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 105382
GnomAD4 exome AF: 0.00000280 AC: 4AN: 1427286Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1AN XY: 706760
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74352
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2023 | Present in an infant with severe HCM who had two other pathogenic variants in the MYBPC3 gene; the R589H variant was found to be on the same allele as the c.3288delG frameshift pathogenic variant (Lekanne Deprez et al., 2006); Not observed at a significant frequency in large population cohorts (gnomAD); 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, 30847666, 16679492, 21750094, 28138913) - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 10, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Hypertrophic cardiomyopathy Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 589 of the MYBPC3 protein (p.Arg589His). 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: 16679492, 21750094, 27476098, 27532257). ClinVar contains an entry for this variant (Variation ID: 42563). 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.Arg589 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been observed in individuals with MYBPC3-related conditions (PMID: 30105547), which suggests that this may be a clinically significant amino acid residue. 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 | Dec 18, 2023 | This missense variant replaces arginine with histidine at codon 589 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 27476098, 27532257, 30297972, 34389451; Makul, 2019, DOI: 10.1016/j.bpj.2018.11.1424). This variant has also been reported in a neonate with hypertrophic cardiomyopathy, who carried another pathogenic truncation variant in the same gene that could explain the observed disease (PMID: 16679492). This variant has been identified in 2/196408 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 | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Apr 01, 2019 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 06, 2014 | The Arg589His variant in MYBPC3 has been identified in 4 individuals with HCM (1 infant, 1 child, 2 adults), three of whom carried other pathogenic variants in MYBPC3 (Lekanne Deprez 2006, Waldmuller 2011, LMM unpublished data). It was abse nt from large population studies. Computational prediction tools and conservatio n analysis do not provide strong support for or against an impact to the protein . In summary, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 01, 2020 | Variant summary: MYBPC3 c.1766G>A (p.Arg589His) results in a non-conservative amino acid change located in the Immunoglobulin subtype domain (IPR003599) 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 1e-05 in 196608 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1766G>A has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy without strong evidence for causality (examples- Lekanne_2006, Waldmuller_2011, van Velzen_2017, Walsh_2017, Ho_2018). In at least one of these publications, the variant was detected in cis with another pathogenic variant (MYBPC3 c.3288delG, p.Glu1096AspfsX93; this patient also carried MYBPC3 c.2827C>T, p.Arg943X in trans- Lekanne_2006). Co-occurrence with MYBPC3 c.3288delG has also been reported in three samples tested in our laboratory (phase unknown), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS- possibly benign.. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 02, 2023 | This missense variant replaces arginine with histidine at codon 589 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21750094, 27476098, 27532257, 30297972, 34389451; Makul, 2019, DOI: 10.1016/j.bpj.2018.11.1424). This variant has also been reported in a neonate with hypertrophic cardiomyopathy, who carried another pathogenic truncation variant in the same gene that could explain the observed disease (PMID: 16679492). This variant has been identified in 2/196408 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 Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2016 | The p.R589H variant (also known as c.1766G>A), located in coding exon 18 of the MYBPC3 gene, results from a G to A substitution at nucleotide position 1766. The arginine at codon 589 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in two individuals with hypertrophic cardiomyopathy (HCM) (Lekanne Deprez RH, J. Med. Genet. 2006 Oct; 43(10):829-32; Waldmüller S, Eur. J. Heart Fail. 2011 Nov; 13(11):1185-92). One of these reports was in an infant with HCM who also carried a nonsense and a frameshift alteration in MYBPC3, which were inherited from unaffected parents (Lekanne Deprez RH, J. Med. Genet. 2006 Oct; 43(10):829-32). 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 variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at