ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.746G>A (p.Arg249Gln) (rs3218713)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000229956 SCV000059652 pathogenic Hypertrophic cardiomyopathy 2014-07-17 criteria provided, single submitter clinical testing The p.Arg249Gln variant in MYH7 has been reported in >10 individuals with hypert rophic cardiomyopathy (HCM), including 2 de novo occurrences, and segregated wit h disease in >30 affected relatives from 3 families (Rosenzweig 1991, Watkins 19 92, Posen 1995, Arbustini 1998, Greber-Platzer 2001, Richard 2003, Woo 2003, Kas sem 2013). Additionally, this variant has been reported by other clinical labor atories in ClinVar (Variation ID: 14088) and was absent from large population st udies. Arginine (Arg) at position 249 is highly conserved in mammals and the ch ange to glutamine (Gln) was predicted to be pathogenic using a computational too l clinically validated by our laboratory. This tool's pathogenic prediction is e stimated to be correct 94% of the time (Jordan 2011). Moreover, this variant is located in the head domain of the MYH7 protein, where studies have shown that va riants in this region have an increased probability for causing disease (Walsh 2 017). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HCM based upon segregation studies, de novo occurrences, and absence from controls. ACMG/AMP criteria applied: PS4, PM6_Strong, PP1_Strong, PM2, PM1, PP3.
GeneDx RCV000158761 SCV000208696 pathogenic not provided 2018-07-23 criteria provided, single submitter clinical testing The R249Q pathogenic variant in the MYH7 gene has previously been reported in numerous unrelated individuals with HCM and has been shown to segregate with disease in more than 20 affected family members from three unrelated families (Rosenzweig et al., 1991; Posen et al., 1995; Arbustini et al., 1998; Woo et al., 2003; Ho et al., 2013; Kassem et al., 2013; Marsiglia et al., 2013; Miller at al., 2013; Murphy et al., 2016; Walsh et al., 2017). In addition, R249Q has been reported as a de novo variant in two unrelated individuals with sporadic HCM (Arbustini et al., 1998; Greber-Platzer et al., 2001). This variant has also been observed in multiple other unrelated indivudals referred for cardiomyopathy genetic testing at GeneDx. The R249Q variant is not observed in large population cohorts (Lek et al., 2016). The R249Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This variant is located in the myosin motor domain, a region enriched with missense variants reported in association with HCM (Walsh et al., 2017; Kelly et al., 2018). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies have demonstrated that R249Q causes defects in ATPase activity (Roopnarine et al., 1998).In summary, R249Q in the MYH7 gene is interpreted as a pathogenic variant.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000015144 SCV000256121 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000229956 SCV000284295 pathogenic Hypertrophic cardiomyopathy 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 249 of the MYH7 protein (p.Arg249Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 23549607, 25351510, 27532257, 27841901), has been shown to  segregate with HCM in several families (PMID: 1944483, 7662452). In addition, this variant has been observed de novo with maternity and paternity confirmed in an individual with hypertrophic cardiomyopathy (PMID: 10065021) and in a proband with left ventricular non-compaction (PMID:24691700). ClinVar contains an entry for this variant (Variation ID: 14088). Experimental studies have shown that this missense change affects the ATPase activity of MYH7 (PMID: 9826622). For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc. RCV000015144 SCV000679802 pathogenic Familial hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617265 SCV000735517 pathogenic Cardiovascular phenotype 2016-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Strong segregation with disease (lod >3 = >10 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Center for Human Genetics,University of Leuven RCV000229956 SCV000886775 pathogenic Hypertrophic cardiomyopathy 2018-10-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762925 SCV000893343 pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2018-10-31 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000158761 SCV000927882 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000853263 SCV000996090 pathogenic Cardiomyopathy 2017-12-13 criteria provided, single submitter clinical testing This variant is well described in patients with hypertrophic cardiomyopathy (PMID: 1430197, 12707239, 12975413) and has been reported by multiple clinical laboratories as pathogenic in the ClinVar database (Variation ID 14088). The p.Arg249Gln variant is located in exon 9 at the active site of the beta-myosin heavy chain functional domain (PMID: 12975413). Functional studies for the p.Arg249Gln variant have shown impairment of ATPase activity and disruption of the actomyosin interaction site in rat models (PMID: 9826622). This variant is absent from population databases, thus it is presumed to be rare. Based on the combined evidence, the p.Arg249Gln variant is classified as pathogenic.
OMIM RCV000015144 SCV000035401 pathogenic Familial hypertrophic cardiomyopathy 1 1992-04-23 no assertion criteria provided literature only
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158761 SCV000280377 pathogenic not provided 2014-10-08 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 p.Arg249Gln (c.746G>A). Based on the data reviewed below we consider this variant very likely disease causing. The variant has been seen in at least 11 unrelated cases of HCM with strong segregation data. The Seidman group first reported the variant segregating with HCM in eight family members with a Lod score of 4.0 (Rosenzweig et al 1991). An additional family reported by Posen et al (1995) also had 8 affected family members with the variant. Arbustini et al (1998) reported a family in which 7 family members with HCM all had both p.Arg249Gln and a mitochondrial variant (tRNAIle A4300G). They also reported an individual with HCM and a de novo p.Arg249Gln variant (he also had an inherited mitochondrial variant). Paternity was confirmed with molecular studies. He had no family history of HCM. Greber-Platzer et al (2001) reported the variant occurring de novo in a child with severe infantile HCM. Her parents and siblings were reported as clinically normal, though it is unclear if they had cardiac evaluations or if paternity was confirmed. Richard et al (2003) reported the variant in three unrelated cases of HCM from their French cohort. Woo et al (2003) reported the variant in three individuals with HCM from a Canadian cohort. Notably, the extent of the decrease in myosin motor activity for MHC Arg403Gln (70–80%), Arg453Cys (70–80%), Arg249Gln (40–50%) and Val606Met (10–15%) correlates well with the cumulative survival rates at 50 years for these mutations (36, 34, 79 and 94%, respectively) [7,45]. Also, the decrease in actin-activated myosin–ATPase rates of rat myosins with the Arg249Gln, Arg403Gln and Val606Met mutations was found to correlate with the severity of clinical phenotype (moderate, severe and mild, respectively) [100]. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging while SIFT predicts it to be deleterious. The arginine at codon 249 is conserved across species, as are neighboring amino acids. Other variants have been reported in association with disease at nearby codons (p.Arg243His, p.Phe244Leu, p.Lys246Gln, p.Gly256Glu). We could find no other disease associated variants at codon 249. In total the variant has not been seen in ~5211 published controls and publicly available population datsets. There is no variation at codon 249 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~5000 Caucasian and African American individuals (as of 1/16/2012). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 1/16/2012). The variant was not observed in the following published control samples: 111 individuals (Arbustini et al 1998), 100 individuals (Richard et al 2003). Early studies on this variant did not report control data.

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