ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1766G>A (p.Arg589His) (rs397515923)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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child, 2 adults), three of whom carried other pathogenic variants in MYBPC3 (Lekanne Deprez 2006, Waldmuller 2011, LMM unpublished data).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 2018-03-29 criteria provided, single submitter clinical testing The R589H variant in the MYBPC3 has been reported previously in association with HCM (Lekanne Deprez et al., 2006; Waldmuller et al., 2011). As mentioned above, R589H was present in an infant with severe HCM who had two other pathogenic variants in the MYBPC3 gene (Lekanne Deprez et al., 2006). Since the R589H variant was on the same allele as the c.3288delG frameshift pathogenic variant, the clinical significance of this variant could not be determined. Waldmuller et al. (2011) also identified the R589H variant in one Caucasian individual diagnosed with HCM, however segregation data is not available. This variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the R589H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.
Invitae RCV000534792 SCV000623532 uncertain significance Hypertrophic cardiomyopathy 2018-06-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 589 of the MYBPC3 protein (p.Arg589His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 16679492, 21750094, 27532257). ClinVar contains an entry for this variant (Variation ID: 42563). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on MYBPC3 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000589649 SCV000696318 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing Variant summary: The c.1766G>A variant affects a conserved nucleotide, resulting in amino acid change from Arg to His. 3/4 in-silico tools predict this variant to be damaging. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not validated by experimental studies yet. Variant of interest has been reported in one HCM patient with occurrence of two other MYBPC3 pathogenic variants (p.Arg943X and c.3288delG, Lekanne_2006) and another HCM patient (Waldmuller_2011). Two individuals tested in our laboratory carried this variant and c.3288delG (scored as DV; phase unknown, likely in cis considering the at least 3 times observance of this co-occurrence-2 internal LCA samples and one reported in Lekanne_2006), suggesting benign outcome. This variant is found in 1/32250 control chromosomes at a frequency of 0.000031, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0010005). In addition, multiple clinical laboratories/reputable databases classified this variant as VUS, without evidence to independantly evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance-possibly benign until additional information becomes available.
Ambry Genetics RCV000620960 SCV000737365 uncertain significance Cardiovascular phenotype 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000611149 SCV000733047 uncertain significance Familial hypertrophic cardiomyopathy 4 no assertion criteria provided clinical testing

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