ClinVar Genomic variation as it relates to human health
NM_002473.6(MYH9):c.5521G>A (p.Glu1841Lys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_002473.6(MYH9):c.5521G>A (p.Glu1841Lys)
Variation ID: 14073 Accession: VCV000014073.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q12.3 22: 36284474 (GRCh38) [ NCBI UCSC ] 22: 36680520 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Apr 15, 2024 Feb 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_002473.6:c.5521G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002464.1:p.Glu1841Lys missense NM_002473.5:c.5521G>A NC_000022.11:g.36284474C>T NC_000022.10:g.36680520C>T NG_011884.2:g.108545G>A LRG_567:g.108545G>A P35579:p.Glu1841Lys - Protein change
- E1841K
- Other names
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- Canonical SPDI
- NC_000022.11:36284473:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MYH9 | - | - |
GRCh38 GRCh37 |
1339 | 1438 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 12, 2018 | RCV000790361.3 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Feb 6, 2024 | RCV001310800.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 27, 2020 | RCV002466403.2 | |
Pathogenic (3) |
criteria provided, single submitter
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- | RCV000015119.35 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 12, 2018)
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criteria provided, single submitter
Method: research
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MYH9-related disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
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NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000891154.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
Comment:
PS4, PP1_strong, PM2, PP4, PP3
Observation 1:
Sex: female
Ethnicity/Population group: European
Observation 2:
Sex: female
Ethnicity/Population group: South-East-Asian
Observation 3:
Number of individuals with the variant: 1
Sex: female
Observation 4:
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Nov 27, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nonsyndromic hearing loss 17
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761487.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
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Pathogenic
(Feb 06, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004242579.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
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Pathogenic
(Dec 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003444534.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Sep 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500741.17
First in ClinVar: Mar 14, 2021 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: yes
Allele origin:
germline
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ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500897.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 17, 2022
Comment:
Submitted to GoldVariant by Jose María Bastida and José Rivera; Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC)
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Clinical Features:
Deafness (present) , Macrothrombocytopenia (present) , Presence of Döhle bodies (present)
Family history: yes
Sex: female
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Likely pathogenic
(Apr 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV003799906.2
First in ClinVar: Feb 13, 2023 Last updated: Mar 04, 2023 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003930255.1
First in ClinVar: Jun 10, 2023 Last updated: Jun 10, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Nov 01, 2001)
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no assertion criteria provided
Method: literature only
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MACROTHROMBOCYTOPENIA AND GRANULOCYTE INCLUSIONS WITH OR WITHOUT NEPHRITIS OR SENSORINEURAL HEARING LOSS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035376.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 30, 2018 |
Comment on evidence:
In 2 unrelated families with May-Hegglin anomaly (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had the same missense mutation, glu1841 to … (more)
In 2 unrelated families with May-Hegglin anomaly (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had the same missense mutation, glu1841 to lys (E1841K), within the coiled-coil domain of the MYH9 protein. The missense mutation was caused by a G-to-A transition at nucleotide 5521 in exon 38. Neither family history nor haplotype analysis suggested common ancestry. Kelley et al. (2000) found the E1841K mutation in 5 of 10 families studied with May-Hegglin anomaly and commented that it occurs at a conserved site in the rod domain. Heath et al. (2001) identified a heterozygous E1841K mutation in 2 unrelated families with Fechtner syndrome. One of the families had been reported by Rocca et al. (1993); in this 4-generation family, only some affected members had 'Alport-like' symptoms, such as deafness, nephritis, and cataracts, consistent with 'reduced expression of Alport manifestations.' (less)
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not provided
(-)
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no classification provided
Method: literature only
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Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV000055832.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Associated with thrombocytopenia, but low risk of developing other disease manifestations over time
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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MYH9-Related Disease. | Adam MP | - | 2021 | PMID: 20301740 |
Clinical, pathological, and genetic analysis of ten patients with MYH9-related disease. | Sun XH | Acta haematologica | 2013 | PMID: 23207509 |
Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. | Franke JD | Blood | 2005 | PMID: 15339844 |
Nonmuscle myosin heavy chain IIA mutations define a spectrum of autosomal dominant macrothrombocytopenias: May-Hegglin anomaly and Fechtner, Sebastian, Epstein, and Alport-like syndromes. | Heath KE | American journal of human genetics | 2001 | PMID: 11590545 |
Mutations in the NMMHC-A gene cause autosomal dominant macrothrombocytopenia with leukocyte inclusions (May-Hegglin anomaly/Sebastian syndrome). | Kunishima S | Blood | 2001 | PMID: 11159552 |
Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly. | Kelley MJ | Nature genetics | 2000 | PMID: 10973260 |
Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium. | Seri M | Nature genetics | 2000 | PMID: 10973259 |
Fechtner syndrome: report of a third family and literature review. | Rocca B | British journal of haematology | 1993 | PMID: 8280620 |
Text-mined citations for rs80338834 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.