Submissions for variant NM_002473.6(MYH9):c.5521G>A (p.Glu1841Lys)

dbSNP: rs80338834

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000790361	SCV000891154	pathogenic	MYH9-related disorder	2018-12-12	criteria provided, single submitter	research	PS4, PP1_strong, PM2, PP4, PP3
CeGaT Center for Human Genetics Tuebingen	RCV001310800	SCV001500741	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	MYH9: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000015119	SCV002500897	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV002466403	SCV002761487	pathogenic	Autosomal dominant nonsyndromic hearing loss 17	2020-11-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001310800	SCV003444534	pathogenic	not provided	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1841 of the MYH9 protein (p.Glu1841Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with MYH9-related disorders (PMID: 10973259, 11159552, 23207509). ClinVar contains an entry for this variant (Variation ID: 14073). 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 not expected to disrupt MYH9 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001310800	SCV003799906	likely pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	The MYH9 c.5521G>A; p.Glu1841Lys variant (rs80338834) is one of the most common MYH9 variants reported in individuals affected with MYH9-related disorders (Hao 2012, Heath 2001, Natesirinilkul 2021, Seri 2000). Pecci et al (2014) reported that in general this variant is not associated with noncongenital manifestations, although others have reported renal and auditory features (Hao 2012). Functional analyses have shown that the variant protein has altered morphology and function (Cechova 2018, Franke 2005, Pal 2020, Zhang 2012). This variant is reported in ClinVar (Variation ID: 14073). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The glutamate at codon 1841 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.912). Based on available information, this variant is considered to be likely pathogenic. References: Cechova S et al. MYH9 E1841K Mutation Augments Proteinuria and Podocyte Injury and Migration. J Am Soc Nephrol. 2018 Jan;29(1):155-167. PMID: 28993503. Franke JD et al. Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. Blood. 2005 Jan 1;105(1):161-9. PMID: 15339844. Hao J et al. A large family with MYH9 disorder caused by E1841K mutation suffering from serious kidney and hearing impairment and cataracts. Ann Hematol. 2012 Jul;91(7):1147-8. PMID: 22080149. Heath KE et al. Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. Am J Hum Genet. 2001 Nov;69(5):1033-45. PMID: 11590545. Natesirinilkul R et al. MYH9 disorder: Identification and a novel mutation in patients with macrothrombocytopenia. Pediatr Blood Cancer. 2021 Jul;68(7):e29055. PMID: 33855781. Pal K et al. Megakaryocyte migration defects due to nonmuscle myosin IIA mutations underlie thrombocytopenia in MYH9-related disease. Blood. 2020 May 21;135(21):1887-1898. PMID: 32315395. Pecci A et al. MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. Hum Mutat. 2014 Feb;35(2):236-47. PMID: 24186861. Seri M et al. Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. Nat Genet. 2000 Sep;26(1):103-5. PMID: 10973259. Zhang Y et al. Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A. Blood. 2012 Jan 5;119(1):238-50. PMID: 21908426.
GeneDx	RCV001310800	SCV003930255	pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the p.(E1841K) variant is sufficient to induce phenotypes observed in MYH9-related disease (Zhang et al., 2012; Cechova et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31922599, 22211851, 23744320, 27353381, 12126520, 26247237, 31064749, 23207509, 22080149, 15339844, 21083612, 23298314, 28993503, 30950024, 21516706, 10973259, 26226608, 31243205, 10973260, 8280620, 11590545, 22558294, 28748566, 22952321, 25077172, 32315395, 33855781, 33188738, 33288657, 35584211, 35764499, 35740994, 37070941, 21908426)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001310800	SCV004242579	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001310800	SCV005199409	pathogenic	not provided	2022-07-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015119	SCV005203185	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2024-07-08	criteria provided, single submitter	clinical testing	Variant summary: MYH9 c.5521G>A (p.Glu1841Lys) results in a conservative amino acid change located in the Myosin tail domain (IPR002928) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250896 control chromosomes. c.5521G>A has been reported in the literature in multiple individuals affected with May-Hegglin anomaly (example, Kelley_2000). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in partial loss of coiled-coil structure of MYH9 in vitro (Franke_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15339844, 10973260). ClinVar contains an entry for this variant (Variation ID: 14073). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000015119	SCV000035376	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2001-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000015119	SCV000055832	not provided	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		no assertion provided	literature only	Associated with thrombocytopenia, but low risk of developing other disease manifestations over time
PreventionGenetics, part of Exact Sciences	RCV000790361	SCV005352033	pathogenic	MYH9-related disorder	2024-07-11	no assertion criteria provided	clinical testing	The MYH9 c.5521G>A variant is predicted to result in the amino acid substitution p.Glu1841Lys. This variant has been reported to be associated with autosomal dominant MYH9-related disorders in many unrelated patients (Seri et al. 2000. PubMed ID: 10973259; Dong et al. 2005. PubMed ID: 16098078; Franke et al. 2005. PubMed ID: 15339844; Poopak et al. 2011. PubMed ID: 21083612). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.