Submissions for variant NM_000256.3(MYBPC3):c.1766G>A (p.Arg589His)

gnomAD frequency: 0.00001  dbSNP: rs397515923

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035430	SCV000059078	uncertain significance	not specified	2014-08-06	criteria provided, single submitter	clinical testing	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child, 2 adults), three of whom carried other pathogenic variants in MYBPC3 (Lekanne Deprez 2006, Waldmuller 2011, LMM unpublished data).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.
GeneDx	RCV000589649	SCV000208045	uncertain significance	not provided	2023-04-15	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534792	SCV000623532	uncertain significance	Hypertrophic cardiomyopathy	2025-01-27	criteria provided, single submitter	clinical testing	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, 37652022). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035430	SCV000696318	uncertain significance	not specified	2020-10-01	criteria provided, single submitter	clinical testing	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..
Ambry Genetics	RCV000620960	SCV000737365	uncertain significance	Cardiovascular phenotype	2016-11-29	criteria provided, single submitter	clinical testing	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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000534792	SCV000995123	uncertain significance	Hypertrophic cardiomyopathy	2019-04-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177054	SCV001341181	uncertain significance	Cardiomyopathy	2023-10-02	criteria provided, single submitter	clinical testing	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.
AiLife Diagnostics, AiLife Diagnostics	RCV000589649	SCV002501952	uncertain significance	not provided	2022-02-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000534792	SCV004842449	uncertain significance	Hypertrophic cardiomyopathy	2023-12-18	criteria provided, single submitter	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000611149	SCV000733047	uncertain significance	Hypertrophic cardiomyopathy 4		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000589649	SCV001925226	uncertain significance	not provided		no assertion criteria provided	clinical testing