ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.5401G>A (p.Glu1801Lys) (rs397516248)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Inherited Cardiomyopathy Variant Curation Expert Panel, RCV000487436 SCV000564459 likely pathogenic Primary dilated cardiomyopathy 2016-12-15 reviewed by expert panel curation The c.5401G>A (p.Glu1801Lys) variant in MYH7 has been reported in 4 individuals with dilated cardiomyopathy, one of whom had additional myopathy features (PS4_Supporting; PMID:19477645; Partners LMM ClinVar SCV000059616.5). Additionally, in two of the probands with dilated cardiomyopathy, the variant occurred de novo (PM6; Partners LMM ClinVar SCV000059616.5). This variant was absent from large population studies (PM2; Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PM2; PM6; PP3; PS4_ Supporting
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211834 SCV000059616 pathogenic Primary dilated cardiomyopathy; Neuromuscular Diseases 2014-11-25 criteria provided, single submitter clinical testing The p.Glu1801Lys variant in MYH7 has been reported in 1 individual with early on set distal myopathy and late onset DCM (Udd 2009) as well as 1 individual with e arly onset distal myopathy and HCM (Lamont 2014). The p.Glu1801Lys variant has a lso been identified by our laboratory in three infants with DCM and occurred de novo in two of them (LMM unpublished data). Additionally, this variant was abse nt from large population studies. Glutamic acid (Glu) is highly conserved in mam mals and across evolutionarily distant species and the change to lysine (Lys) wa s predicted to be pathogenic using a computational tool, which was validated by our laboratory using a set of cardiomyopathy variants with well-established clin ical significance. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant meets our criteria to be classified as pathogenic for Laing distal myopathy with cardiomyopathy in an au tosomal dominant manner ( base d upon absence from controls and multiple de novo occurrences.
GeneDx RCV000158700 SCV000208635 likely pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing The E1801K likely pathogenic variant in the MYH7 gene has been reported in a Moldavian family with early onset distal myopathy and later onset, severe DCM (Udd et al., 2009). Lamont et al. (2014) also found E1801K in two members of an Israeli family with distal muscle weakness, and the proband was diagnosed with HCM at age 23. Ruggiero et al. (2015) identified the E1801K variant in three members of an Italian family with cardiomyopathy and distal myopathy. Additionally, E1801K has been observed in two infants tested at GeneDx for DCM. In each case, parental testing did not identify the E1801K variant, suggesting that these events occurred de novo. Similarly, the Laboratory for Molecular Medicine reports that E1801K has been observed in three infants with DCM tested at their laboratory, and was de novo in two of these cases (ClinVar SCV000059616.4; Landrum et al.,2016). E1801K results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts E1801K is probably damaging to the protein structure/function. Furthermore, E1801K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although a variant at this same residue (E1801G) has been reported in association with cardiomyopathy (Stenson et al., 2014), the clinical significance of this variant has not been definitively determined. Therefore, this variant is likely pathogenic.
Blueprint Genetics RCV000207999 SCV000264100 pathogenic Left ventricular noncompaction cardiomyopathy 2015-08-20 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000132759 SCV000680306 pathogenic Myopathy, distal, 1 2017-12-13 criteria provided, single submitter clinical testing
Invitae RCV000699484 SCV000828197 pathogenic Hypertrophic cardiomyopathy 2018-04-24 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1801 of the MYH7 protein (p.Glu1801Lys). 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 several families segregating with disease (PMID:27387980, 25576864) and in multiple unrelated individuals affected with dilated cardiomyopathy, left ventricular noncompaction, and skeletal muscle disease (PMID: 24503780, 27532257, 28855170, 24664454, 19477645). ClinVar contains an entry for this variant (Variation ID: 43069). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Neurogenetics Laboratory,Royal Perth Hospital RCV000132759 SCV000119910 pathogenic Myopathy, distal, 1 2013-01-01 no assertion criteria provided clinical testing
GeneReviews RCV000132759 SCV000223110 pathogenic Myopathy, distal, 1 2015-03-12 no assertion criteria provided literature only

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