ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1750G>C (p.Gly584Arg) (rs121913626)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000471604 SCV000564418 pathogenic Hypertrophic cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.1750G>C (p.Gly584Arg) variant in MYH7 has been reported in >25 individuals with hypertrophic cardiomyopathy (PS4; PMID:1552912; PMID:10567705; PMID:24093860; Partners LMM ClinVar SCV000059395.5; SHaRe consortium, PMID: 30297972). This variant segregated with disease in >5 affected individuals (PP1_Moderate; PMID:1552912; Partners LMM ClinVar SCV000059395.5). This variant was absent from large population studies (PM2; This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS4; PM1; PM2; PP1_Moderate; PP3
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000471604 SCV000059395 pathogenic Hypertrophic cardiomyopathy 2015-06-03 criteria provided, single submitter clinical testing The p.Gly584Arg variant in MYH7 has been reported in 8 individuals with HCM (Wat kins 1993, Nier 1999, Santos 2012, Marsiglia 2013) and has been identified by ou r laboratory in >20 individuals with HCM. Furthermore, this variant segregated w ith disease in 4 affected members (including 1 obligate carrier) of 4 families ( Watkins 1993, LMM unpublished data). This variant has also been reported by othe r clinical laboratories in ClinVar (Variation ID 14090) and was identified in 1/ 111720 European chromosomes by the Genome Aggregation Database (gnomAD, http://g; dbSNP rs121913626). In vitro functional studies provi de some evidence that this variant may impact protein function (Fujita 1998, Wan g 2003). Finally, glycine (Gly) at position 584 is highly conserved in evolution and the change to arginine (Arg) was predicted to be pathogenic using a computa tional tool clinically validated by our laboratory. This tool's pathogenic predi ction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets criteria to be classified as pathogenic for HCM in an autosomal d ominant manner based upon presence in segregation studies, multiple reports in H CM probands, some functional and computational evidence and very low frequency i n the general population. ACMG/AMP Criteria applied (Richards 2015): PS4, PP1_Mo derate, PM2, PP3, PS3_Supporting.
GeneDx RCV000223743 SCV000208751 pathogenic not provided 2016-10-27 criteria provided, single submitter clinical testing The G584R variant has been reported previously in association with HCM (Erdmann et al., 2003). Erdmann et al. reported this variant in an individual diagnosed with HCM and showed that it was absent in 100 chromosomes from healthy unrelated control subjects. Furthermore, G584R was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Another missense variant that alters the same residue (G584S), as well as missense variants in nearby residues (A583V and D587V), have been reported in association with HCM, further supporting the functional importance of this residue and this region of the protein. Moreover, Rayment et al. (1995) suggested that variants affecting the G584 residue may modify the nature and timing of conformational changes during the contractile cycle. In summary, G584R variant in the MYH7 gene is interpreted as a disease-causing variant.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000015146 SCV000256138 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000471604 SCV000546174 pathogenic Hypertrophic cardiomyopathy 2019-03-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 584 of the MYH7 protein (p.Gly584Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature as co-segregating with disease in families affected with hypertrophic cardiomyopathy (PMID: 8250038), as well as in multiple unrelated affected individuals (PMID: 22429680, 24093860). ClinVar contains an entry for this variant (Variation ID: 14090). Experimental studies have shown that this missense change impairs actin filament movement in vitro (PMID: 12953063). A different missense substitution at this codon (p.Gly584Ser) has been determined to be pathogenic (PMID: 12974739, 23283745, 24510615, 26187847). This suggests that the glycine 584 residue is critical for MYH7 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a rare missense change that has been reported to co-segregate with disease in families, and in multiple unrelated affected individuals. It has also been shown to affect protein function and it is located in a residue important for protein function. For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000035744 SCV000577980 pathogenic Primary familial hypertrophic cardiomyopathy 2016-10-24 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170509 SCV001333092 pathogenic Cardiomyopathy 2018-09-11 criteria provided, single submitter clinical testing
OMIM RCV000015146 SCV000035403 pathogenic Familial hypertrophic cardiomyopathy 1 1992-04-23 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000223743 SCV000280304 likely pathogenic not provided 2014-10-07 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYH7 c.1750G>C p.Gly584Arg g.23896932C>G (chr14.GRCh37) Seen in 1 pt with HCM in our center. First reviewed 4/1/2013, re-reviewed 1 oct 2014 While the variant has been seen in many cases of cardiomyopathy, we consider it likely pathogenic instead of very likely pathogenic because of the absence of a large number of controls matching the published cases (which are nearly all Portuguese) as well as the lack of strong segregation data or animal model data. In total this variant has been seen in at least 29 unrelated individuals with HCM (including one patient in our center) with weak segregation data in two families. We have seen the variant once in our center, in a Portuguese man who was diagnosed at 58 years of age with HCM, with a septum of 3.1 cm. This variant was initially reported in two families with HCM (Watkins et al 1993). In one family a haplotype block containing the variant segregated with 3 affected individuals, and in the second family it segregated with 2 affecteds. Both families were of Portuguese origin, and they had identical haplotypes thus suggesting p.Gly584Arg is a founder variant in this population. In a study on 80 Portuguese patients with HCM Santos et al (2012) observed the variant in one individual with HCM. Vieira et al (1995) appear to have assessed the prevalence of this variant in a Portuguese population. The manuscript is in Portuguese. Using google translate we were able to ascertain that they did not observe this variant in their cohort, but unfortunately it is unclear how many patients they studied or if they published controls. GeneDx shared that they have seen this variant in two other probands, one Caucasian and the other Portuguese. I also contacted the Laboratory for Molecular Medicine and they shared that they have seen it in 23 cases (2013). Unfortunately they have no segregation data nor do they have detailed ancestry data. They shared that most of the cases were listed as Caucasian without further specifics, though they did notice that many of the patients have Portuguese names. Carolyn Ho’s group included a patient with this variant in a paper on extracellular volume expansion, however it is unclear if that individual had hypertrophy or not (Ho et al 2013). In addition, that case likely overlaps with the LMM’s cases. No ancestry or segregation data was reported. Per their ClinVar submissions, LMM classifies it as likely pathogenic (SCV000059395). This is a semi conservative amino acid change with a nonpolar, neutral Glycine replaced with a polar, positively charged Arginine. In silico analysis (SIFT, PolyPhen2, mutationtaster) predicts the amino acid change to be deleterious/probably damaging to the resulting protein. The Laboratory of Molecular Medicine shared that their sarcomere-specific PolyPhen predicts the variant to be pathogenic and the lab notes that the pathogenic prediction is estimated to be correct 94% of the time (Jordan et al 2011). Additional variants at the same codon (p.Gly584Ser (Erdmann et al 2003, per ClinVar LMM classifies as likely pathogenic (SCV000059394)) and nearby codons (p.His576Arg, p.Ala583Val, p.Asp587Val) have been reported in association with cardiomyopathy (per the GeneDx report citing HGMD). Wang et al (2003) observed dramatic myofibril disarray after introducing the variant into chicken embryonic myocytes. Nier et al (1999) studied muscle fibers from a patient with p.Gly584Arg and observed that only 12% of all myosin in the sarcomeres was the variant version. However they did not observe any impact on sarcomere function. In total the variant has not been seen in ~6600 published controls and publicly available general population samples. GeneDx did not report internal control data for this variant. The variant is listed in dbSNP (rs121913626) and 1000Genomes however there is no population frequency data available. The variant is not currently listed in the NHLBI Exome Sequencing Project dataset, which includes variant calls on ~6500 Caucasian and African American individuals (as of October 1 2014). Santos et al (2012) did not observe the variant in 100 control individuals (origin is not listed but the study was done in Portugal).

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