ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys) (rs121913628)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158573 SCV000208508 pathogenic not provided 2017-02-03 criteria provided, single submitter clinical testing The E924K pathogenic variant in the MYH7 gene has been published multiple times in association with HCM (Watkins et al., 1992; Morner et al., 2003; Van Driest et al., 2004; Song et al., 2005; Kaski et al., 2009; Liu et al., 2013; Marsiglia et al., 2013). E924K was first described in a female proband and her affected daughter, and was not detected in 180 control chromosomes (Watkins et al., 1992). Later studies reported E924K to be present in several other unrelated probands with HCM, and did not detect the pathogenic variant in more than 600 control chromosomes of varying ethnic backgrounds (Morner et al., 2003; Van Driest et al., 2004; Song et al., 2005; Kaski et al., 2009; Liu et al., 2013; Marsiglia et al., 2013). Additionally, E924K in the MYH7 gene has been reported as a pathogenic variant in the ClinVar Database (Landrum et al., 2014), and E924K has been observed in multiple other unrelated individuals tested for HCM at GeneDx. Furthermore, the NHLBI Exome Sequencing Project reports E924K was not observed in approximately 6,500 samples from individuals of European and African American ancestry, indicating it is not a common benign variant in these populations.The E924K pathogenic variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species. Consequently, in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies demonstrated that E924K, which lies in the S2 segment of the myosin rod, completely abolishes normal binding to MYBPC3 (Gruen et al., 1999). Moreover, another missense pathogenic variant in this same residue (E924Q) and in nearby residues (E921K, E927K, D928N, D928V) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein.In summary, E924K in the MYH7 gene is interpreted as a pathogenic variant.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000015148 SCV000212642 pathogenic Familial hypertrophic cardiomyopathy 1 2014-09-09 criteria provided, single submitter research This MYH7 Glu924Lys variant has been identified in multiple unrelated HCM cases. It was first described by Watkins et al. (1992a & 1992b) as a de novo variant in a HCM case whose daughter was also genetically and clinically affected. This variant is absent in general population databases including 1000 genomes project (http://www.1000genomes.org/), and the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). An in vitro functional study has shown the MYH7 Glu924Lys completely disrupts binding to another sarcomere protein - MYBPC3 (Gruen M, et al., 1999). We have identified the MYH7 Glu924Lys variant in one case of familial HCM in our cohort. Family screening identified all clinically affected members (n=3) to be carriers of the variant. Based on evidence that the de novo variant is causal of HCM (Watkins et al., 1992a & 1992b; Morita H, et al., 2008), other literature, and its absence in the general population, we classify this variant as "pathogenic".
Invitae RCV000197762 SCV000253817 pathogenic Hypertrophic cardiomyopathy 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 924 of the MYH7 protein (p.Glu924Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in multiple families and individuals affected with hypertrophic cardiomyopathy (PMID: 12818575, 15358028, 1552912, 27247418) including reports in affected individuals where this variant was observed to occur de novo (PMID: 1430197, 15563892). ClinVar contains an entry for this variant (Variation ID: 14092). 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). Experimental studies have shown that this missense change affects MYBPC3 binding capabilities in vitro (PMID: 10024460). In summary, this variant has been reported in several affected individuals and has been shown to affect protein function. For these reasons it has been classified as Pathogenic.
Laboratory of Genetics and Molecular Cardiology,University of São Paulo RCV000015148 SCV000256135 likely pathogenic Familial hypertrophic cardiomyopathy 1 criteria provided, single submitter clinical testing
Ambry Genetics RCV000252292 SCV000319014 pathogenic Cardiovascular phenotype 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000015148 SCV000778596 pathogenic Familial hypertrophic cardiomyopathy 1 2017-11-28 criteria provided, single submitter research
Fulgent Genetics,Fulgent Genetics RCV000762922 SCV000893340 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
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770489 SCV000901933 pathogenic Cardiomyopathy 2017-02-20 criteria provided, single submitter clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health,University of California San Diego RCV000197762 SCV000995146 pathogenic Hypertrophic cardiomyopathy 2017-09-12 criteria provided, single submitter clinical testing
OMIM RCV000015148 SCV000035405 pathogenic Familial hypertrophic cardiomyopathy 1 1992-04-23 no assertion criteria provided literature only
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000197762 SCV000059475 pathogenic Hypertrophic cardiomyopathy 2013-03-20 no assertion criteria provided clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000158573 SCV000280335 likely pathogenic not provided 2015-07-23 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. Glu924Lys (E924K; G>A at the nucleotide level) This variant has been reported in at least 6 unrelated cases of HCM with weak segregation data in one family and just one functional study. Watkins et al. (1992, NEJM and J Clin Invest) detected a de novo Glu924Lys variant in one HCM case of European descent, with transmission of both the variant and the disease to an offspring. [Solomon et al. (1993) may be referring to these same two patients.] Morner et al. (2003) found the variant in one case in Sweden, in a patient who also carried the MYBPC3 variant Val896Met. Van Driest et al. (2004) detected the Glu924Lys variant in one case of HCM at the Mayo Clinic. Xie et al. (2004) apparently found it in a Chinese family, but the article is in Chinese so this can’t be confirmed. Song et al. (2005) found it in 2 unrelated Chinese cases of HCM. Morita et al. (2008) found it had occurred de novo in a sporadic HCM patient. Both parents were clinically unaffected. Kaski et al. (2009) identified it in an HCM patient. There is functional data available: Gruen & Gautel (1999) showed the variant to significantly reduce myosin binding to MYBPC. Another change at this same codon, Glu924Gln, has been associated with HCM (Harvard Sarcomere Protein Gene Mutation Database). Variation at nearby loci of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Glu921Lys, Glu927Lys, Asp928Asn, Glu930Lys, and Glu931Lys (Harvard Sarcomere Protein Gene Mutation Database). This is a nonconservative amino acid change from an acidic, negatively-charged Glutamic Acid to a basic, positively-charged Lysine. The Glutamic Acid at codon 924 is completely conserved across 44 vertebrate species examined. Some surrounding residues are also highly conserved. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “probably damaging”. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995). In total this Glu924Lys variant has not been seen in ~6190 published controls and publicly available population datasets. No variation codon 924 is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~3500 Caucasian and ~1800 African American individuals (as of 1/15/2012). There is no variation at this codon listed in dbSNP or in 1000 genomes (as of 1/15/2012). The variant was not observed in published controls: Watkins et al. (1992) did not observe the variant in 90 (Caucasian?) controls. Morner et al. (2003) did not find it in 100 controls. Van Driest et al. (2004) did not observe the variant in 100 Caucasian and 100 African American controls. Song et al. (2005) did not find it in 120 Chinese controls. Morita et al. (2008) did not find it in 180 ethnicity-matched controls. Kaski et al. (2009) did not find it in 200 controls.

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