ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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segregated with disease in one affected relative (Song 2005, Olivotto 2008, Gir olami 2010, Adalsteinsdottir 2014, LMM unpublished data).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.
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.
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.
Integrated Genetics/Laboratory Corporation of America RCV000845415 SCV000696345 likely pathogenic Primary familial hypertrophic cardiomyopathy 2019-11-27 criteria provided, single submitter clinical testing Variant Summary: MYH7 c.2606G>A (p.Arg869His) results in a non-conservative amino acid change located in the Myosin tail domain (IPR002928). Five of five in-silico tools predict a damaging effect of the variant on protein function (ACMG PP3, PP2). The variant allele was found at a frequency of 2.4e-05 in 251440 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2606G>A has been reported in the literature in several well phenotyped individuals affected with and meeting established clinical criteria for Hypertrophic Cardiomyopathy (HCM) (e.g. Witjas-Paalberends_2013, Adalsteinsdottir_2014, Olivotto_2011, Girolami_2010, Walsh_2017, Ho_2018). Though the variant was reported to co-occur with other pathogenic MYBPC3 variants in two different families, the double heterozygous patients showed an earlier onset of HCM, a more rapid disease progression with a more severe phenotype than heterozygous variant carriers, which might be consistent with an additive effect for the co-occurring variants (Girolami_2010, Olivotto_2011). A recent study reported that the allele frequency of this variant in a cohort of HCM patients is much higher (0.0076; i.e. 42/5526 alleles) than that in controls (6/251440 in gnomAD), suggesting this variant could be associated with HCM (Ho_2018) (ACMG PS4). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions (evaluation after 2014) cite the variant: four times as likely pathogenic and once as uncertain significance. In addition, other variants affecting the same codon, R869C, R869G, R869L, have been reported in HGMD in association with HCM (ACMG PM1). Based on the evidence outlined above the variant was re-classified as likely pathogenic.
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.
Blueprint Genetics RCV000587299 SCV000928012 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000845415 SCV000987483 likely pathogenic Primary familial hypertrophic cardiomyopathy criteria provided, single submitter clinical testing
Cardiology unit,Meyer University Hospital RCV000845415 SCV001147002 pathogenic Primary familial hypertrophic cardiomyopathy 2020-01-27 criteria provided, single submitter clinical testing The MYH7:Arg869His variant has been implicated in HCM in several studies (Van Driest et al, 2004; Girolami et al., 2006, Olivotto et al., 2008; Girolami et al., 2010; Witjas-Paalberens et al., 2013; Marsiglia et al., 2013; Adalsteinsdottir et al., 2014; Bos et al., 2014; Mazzarotto & Girolami et al., 2018). This variant is sufficiently rare in the gnomAD population database (MAF 2.39E-5) to activate the PM2 moderate criteria for rarity as per the ACMG/AMP variant interpretation guidelines adapted for MYH7 variants in cardiomyopathy (Kelly et al., 2018). The Arg869His variant alters a residue within the myosin head, which constitutes a large hotspot for variants with a high prior likelihood of pathogenicity in HCM characterised by etiological fraction >0.95 (Kelly et al., 2018 defines ita s between residues 181-937; Walsh et al., 2019 as 167-931), causing the activation of the PM1 criteria (Kelly et al., 2018). Furthermore, we found evidence of co-segregation with HCM in a large Italian pedigree comprising 7 affected carriers and 1 deceased obligate carrier reported to be affected. This enables activation of the PP1_strong criteria for observing >=7 meioses (Kelly et al., 2018). This variant is also carried by 30 of 1198 unrelated probands with HCM tested at the nearby Careggi University Hospital as opposed to 0 of 356 non-HCM probands tested in the same lab (p=6.22E-4), enabling activation of the PS4_strong criteria (Mazzarotto & Girolami et al., 2018; Kelly et al., 2018). Computational evidence is also to be considered supportive of pathogenicity, as multiple in silico pathogenicity predictors classify this variant as damaging / deleterious, enabling activation of the PP3 criteria supporting pathogenicity. In conclusion, the activation of 2 strong, 2 moderate and 1 supporting criteria in favour of pathogenicity enables classification of the MYH7:Arg869His variant as pathogenic for HCM.

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