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 2021-02-22 criteria provided, single submitter clinical testing Reported in a Saudi Arabian infant with DCM and her mildly-affected mother; the infant also harbored a paternally-inherited variant in the LAMA4 gene (Abdallah et al., 2019); Identified in numerous other individuals referred for HCM genetic testing at GeneDx and found to segregate with disease in at least two families; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 14092; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies have demonstrated that E924K, which lies in the S2 segment of the myosin rod, completely abolishes normal binding to MYBPC3 (Gruen et al., 1999); This variant is associated with the following publications: (PMID: 7731997, 25125180, 24093860, 28606303, 16630449, 25351510, 1430197, 30775854, 10024460, 21425739, 23074333, 21310275, 25524337, 22857948, 15358028, 12818575, 18403758, 23711808, 22455086, 18409188, 1552912, 27247418, 28166811, 27532257, 15563892, 20031618, 24510615, 22429680, 15569455, 29743414, 31006259, 30650640)
Invitae RCV000197762 SCV000253817 pathogenic Hypertrophic cardiomyopathy 2020-08-14 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 2018-06-25 criteria provided, single submitter clinical testing The p.E924K pathogenic mutation (also known as c.2770G>A), located in coding exon 21 of the MYH7 gene, results from a G to A substitution at nucleotide position 2770. The glutamic acid at codon 924 is replaced by lysine, an amino acid with similar properties. This alteration has been reported across ethnicities in individuals with hypertrophic cardiomyopathy (HCM), including at least two de novo cases (Watkins H et al. J. Clin. Invest., 1992 Nov;90:1666-71; Morita H et al. N. Engl. J. Med., 2008 May;358:1899-908; Fokstuen S et al. Hum. Mutat., 2008 Jun;29:879-85; Santos S et al. BMC Med. Genet., 2012 Mar;13:17). Segregation with disease in affected family members has also been described (Watkins H et al. J. Clin. Invest., 1992 Nov;90:1666-71; Liu WL et al. Zhonghua Xin Xue Guan Bing Za Zhi, 2006 Mar;34:202-7). Additionally, this alteration has been reported in HCM cohorts, although clinical details were limited (Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Lopes LR et al. Heart, 2015 Feb;101:294-301; Walsh R et al. Genet. Med., 2017 Feb;19:192-203). Functional studies in rat cardiomyocytes have shown no apparent structural changes, but total loss of MyBP-C binding was observed (Gruen M. J. Mol. Biol. 1999 Feb;286:933-949). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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; MYH7-related late-onset scapuloperoneal muscular dystrophy 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
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000197762 SCV000212642 pathogenic Hypertrophic cardiomyopathy 2020-02-25 no assertion criteria provided 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. We have identified the MYH7 Glu924Lys variant in 2 HCM probands (Ingles et al., 2017). One proband has two clinically affected family members who also harbour the variant. This variant is absent from the Genome Aggregation Database ( An in vitro functional study has shown the MYH7 Glu924Lys completely disrupts binding to another sarcomere protein - MYBPC3 (Gruen M, et al., 1999). In a large HCM population study Walsh et al., showed that MYH7 variants identified in HCM cases were found to cluster between amino acids 181- 937 (2017), this implies that variants in this region are likely to cause a HCM phenotype. Based on the adapted ACMG criteria (Kelly MA, et al., 2018) this variant has been reported in at least 15 probands (PS4), is located in the 'hotspot' of MYH7 (PM1), is rare in the general population (PM2), as been reported in a de novo case (PM6), segregates with disease (PP1_moderate) and multiple in silico tools predict that this variant is deleterious (PP3), therefore we classify MYH7 Gly924Lys as 'pathogenic'.
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 ( 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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