NM_002473.6:c.5521G>A

Variant names:

• chr22-36284474-C-T
• rs80338834
• NM_002473.6:c.5521G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_002473.6(MYH9):​c.5521G>A​(p.Glu1841Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 7.58

Genes affected

MYH9 (HGNC:7579): (myosin heavy chain 9) This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MYH9 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 84 curated benign missense variants. Gene score misZ: 3.473 (above the threshold of 3.09). Trascript score misZ: 6.1231 (above the threshold of 3.09). GenCC associations: The gene is linked to May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 22-36284474-C-T is Pathogenic according to our data. Variant chr22-36284474-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36284474-C-T is described in Lovd as [Pathogenic]. Variant chr22-36284474-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH9	NM_002473.6	c.5521G>A	p.Glu1841Lys	missense_variant	Exon 39 of 41	ENST00000216181.11	NP_002464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH9	ENST00000216181.11	c.5521G>A	p.Glu1841Lys	missense_variant	Exon 39 of 41	1	NM_002473.6	ENSP00000216181.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

May 19, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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) -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYH9: PP1:Strong, PM1, PM2, PS3:Moderate, PS4:Moderate -

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:3 Other:1

Jul 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

-

ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Associated with thrombocytopenia, but low risk of developing other disease manifestations over time -

Nov 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

MYH9-related disorder Pathogenic:2

Dec 12, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4, PP1_strong, PM2, PP4, PP3 -

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: 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. -

Autosomal dominant nonsyndromic hearing loss 17 Pathogenic:1

Nov 27, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Deafness Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4,PS3,PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.83		Gain of methylation at E1841 (P = 0.0159);
MVP		0.92
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.67
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80338834; hg19: chr22-36680520;