ClinVar Miner

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

dbSNP: rs3218713
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 2021-11-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek et al., 2016); Published functional studies demonstrate abnormal ATPase activity and decreased muscle contractibility (Roopnarine et al., 1998; Adhikari et al., 2019; Bell et al., 2019); This variant is associated with the following publications: (PMID: 24093860, 10065021, 27247418, 10521296, 25611685, 23283745, 23396983, 24805292, 30206291, 30685992, 28481356, 31980526, 24298987, 9826622, 1944483, 23233322, 11133230, 12975413, 26914223, 27532257, 7662452, 12707239, 7731997, 23054336, 22112859, 23549607, 29212898, 30767072, 30950055, 31397097, 31513939, 31213605, 31019026, 27841901, 33407484, 29300372)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000015144 SCV000256121 likely pathogenic Hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Invitae RCV000229956 SCV000284295 pathogenic Hypertrophic cardiomyopathy 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 249 of the MYH7 protein (p.Arg249Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy and/or left ventricular non-compaction (PMID: 1944483, 7662452, 10065021, 23549607, 24691700, 25351510, 27532257, 27841901). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14088). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MYH7 function (PMID: 9826622). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Phosphorus, Inc. RCV000015144 SCV000679802 pathogenic Hypertrophic cardiomyopathy 1 2017-08-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000617265 SCV000735517 pathogenic Cardiovascular phenotype 2021-10-21 criteria provided, single submitter clinical testing The p.R249Q pathogenic mutation (also known as c.746G>A), located in coding exon 7 of the MYH7 gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by glutamine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This mutation has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM), including two de novo cases, and has segregated with disease in multiple families (e.g., Rosenzweig A et al. N. Engl. J. Med. 1991;325:1753-60; Posen BM et al. Br Heart J. 1995;74:40-6; Arbustini E et al. Heart. 1998;80:548-58; Greber-Platzer S et al. J. Mol. Cell. Cardiol., 2001;33:141-8; Otsuka H et al. Circ. J. 2012;76:453-61; Kassem HSh et al. J Cardiovasc Transl Res. 2013;6:65-80; Marsiglia JD et al. Am. Heart J. 2013;166:775-82). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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 Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000853263 SCV001333349 pathogenic Cardiomyopathy 2019-01-09 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Region Ostergotland RCV000015144 SCV002522546 pathogenic Hypertrophic cardiomyopathy 1 2019-04-08 criteria provided, single submitter clinical testing PS2, PS4, PM2, PP1, PP3, PP5
CeGaT Center for Human Genetics Tuebingen RCV000158761 SCV002545164 likely pathogenic not provided 2022-05-01 criteria provided, single submitter clinical testing MYH7: PM1, PM2, PP2, PS3:Supporting, PS4:Supporting
3billion RCV000015144 SCV003841992 pathogenic Hypertrophic cardiomyopathy 1 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:. 29300372.). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014088). Different missense changes at the same codon (p.Arg249Gly, p.Arg249Leu) have been reported to be associated with MYH7 related disorder (ClinVar ID: VCV000635223 / PMID: 24691700). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM RCV000015144 SCV000035401 pathogenic 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.
Genomics England Pilot Project, Genomics England RCV000015144 SCV001760334 likely pathogenic Hypertrophic cardiomyopathy 1 no assertion criteria provided clinical testing

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