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

dbSNP: rs3218713

Total submissions: 17

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