ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2606G>A (p.Arg869His) (rs202141173)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000587299 SCV000928012 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing
GeneDx RCV000587299 SCV000208488 likely pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing The R869H likely pathogenic variant in the MYH7 gene has been reported multiple times in association with HCM (Van Driest et al, 2004; Olivotto et al., 2008; Girolami et al., 2010; Adalsteinsdottir et al., 2014; Bos et al., 2014). Olivotto et al. (2008) observed this variant in 10 individuals from at least two families with HCM; however, affected individuals harbored other cardiogenetic variants. In addition, a 32-year old woman with HCM was reported to be heterozygous for 3 distinct variants, including R869H in MYH7, Q258K in MYBPC3, and A86fs in TNNI3; her mother, who only harbored the MYH7 R869H variant, had mild asymmetric septal hypertrophy (Girolami et al., 2010). Additionally, the R869H variant in the MYH7 gene has been reported in other unrelated individuals with HCM (Bick et al., 2012; Witjas-Paalberends et al., 2013; Marsiglia et al., 2013; Coppini et al., 2014; Lopes et al., 2015). Furthermore, the R869H variant has segregated with HCM in a large family tested at GeneDx.R869H affects the binding site for the myosin-binding proteins (MyBP-C) of the S2 segment of the myosin rod (Cuda et al., 1997). Other variants affecting the same residue (R869C, R869G) and nearby residues (R870C, R870H, R870L) have been reported in association with HCM in the Human Gene Mutation Database (Stenson et al., 2014). Functional studies of some of the variants in this region demonstrated decreased actin filament movement (Cuda et al., 1997) and drastically reduced MyBP-C binding (Gruen et al., 1999). Additionally, in silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Finally, The R869H variant is not observed at any significant frequency in large population cohorts (Lek et al., 2016). In summary, R869H in the MYH7 gene is interpreted as a likely pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709745 SCV000840020 likely pathogenic Familial hypertrophic cardiomyopathy 1 2017-07-06 criteria provided, single submitter clinical testing This c.2606G>A (p.Arg869His) variant in the MYH7 gene has been reported in several patients with hypertrophic cardiomyopathy [PMID 18533079, 20359594, 24793961, 14676227, 27247418, 25078086]. Cosegregation has been reported but no detailed information was available for review [PMID 18533079]. This variant was also reported in a patient with hypertrophic cardiomyopathy diagnosed at 18 years of age [PMID 20359594 ]. The patient carries a frameshift variant in TNNI3 and a missense in MYBPC3, both inherited from the father; and this variant in MYH7, inherited from the mother. The mother had mild asymmetric septal hypertrophy. Additional patients have been reported with a change affecting the same amino acid position (Arg869Cys, Arg869Gly). While not validated for clinical use, computer-based algorithms yield discrepant results regarding the deleterious effect of this p.Arg869His change. However, this variant is highly conserved in mammal. This variant has been observed in 6 heterozygous individuals in the gnomAD database (http://gnomad.broadinstitute.org/variant/14-23894051-C-T). This variant is thus classified as likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587299 SCV000696345 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing Variant summary: The MYH7 c.2606G>A (p.Arg869His) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in the myosin tail domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in hte large control database ExAC at a frequency of 0.000033 (4/121390 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MYH7 variant (0.0010005). The variant has been identified in numerous hypertrophic cardiomyopathy (HCM) patients in the literature (e.g., Adalsteinsdottir_Circ_2014; Witjas-Paalberends_Cardio Res_2013; Bos_MCP_2014; Olivotto_J Am College Cardiol_2011; among others), however, without strong evidence for pathogenicity. Two independent patients/families have been identified whom carry the variant along with co-occurring pathogenic mutations in MYBPC3 (c.3192dupC, p.Lys1065FlnfsX12, pathogenic; c.772G>A, p.Glu258Lys, pathogenic). A study on these families suggested the variant likely contributes to the development of HCM, since in one of the families a mother of a severely affected proband (who carried 3 different HCM variants including the variant of interest) carried only the variant of interest and was mildly affected (Girolami_JACC_2010). The same publication analyzed the second family where it was observed that those who carried the variant were more severely affected than those who did not carry the variant. Homburger_PNAS_2016 reported the allele frequency of this variant in a cohort of HCM patients (0.0057, 33/5826), and Walsh_GIM_2017 reported its allele frequencies in two independent cohorts of HCM patients (0.00016 and 0.00017). All frequencies are higher than that in ExAC controls (0.000033), suggesting this variant may associate with HCM. Several overlapping and adjacent variants (p.R869C, p.R869G, p.R869L, p.A868P, p.R870C, p.R870H, and p.R870L) are reported in HGMD and classified as disease mutations, suggesting the region may be a hotspot for mutation and critical to gene function. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as VUS in ClinVar, though two other clinical diagnostics laboratories recently classified the variant as "Class 4-Likely pathogenic" (Oxford Medical Genetics Lab) and "VUS favour pathogenic" (Partners Laboratory for Molecular Medicine) in a publication (Walsh_GIM_2017). Taken together, this variant is classified as VUS-possibly pathogenic.
Invitae RCV000458948 SCV000546244 likely pathogenic Hypertrophic cardiomyopathy 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 869 of the MYH7 protein (p.Arg869His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs202141173, ExAC 0.02%). This variant has been reported in multiple individuals affected with hypertrophic cardiomyopathy (PMID: 15358028, 16858239, 23674513, 24093860, 24793961, 25078086, 27247418, 27532257). However, in at least one individual affected with hypertrophic cardiomyopathy, a pathogenic variant was also identified in another cardiomyopathy-related gene (PMID: 20359594). ClinVar contains an entry for this variant (Variation ID: 177667). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000458948 SCV000203912 likely pathogenic Hypertrophic cardiomyopathy 2016-04-25 criteria provided, single submitter clinical testing The p.Arg869His variant in MYH7 has been reported in 15 individuals with HCM and segregated with disease in one affected relative (Song 2005, Olivotto 2008, Gir olami 2010, Adalsteinsdottir 2014, LMM unpublished data). It has been identified in 2/10400 African and 2/66732 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202141173). This variant was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, although additional studies are requi red to fully establish its clinical significance, the p.Arg869His variant is lik ely pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845415 SCV000987483 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing

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