PS4, PM2, PP1_strong, PP4, PP3
ClinVar Genomic variation as it relates to human health
NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys)
Germline
Classification
Help
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.
(15)
Help
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.
Pathogenic
15
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys)
Variation ID: 14074 Accession: VCV000014074.52
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 22q12.3 22: 36295069 (GRCh38) [ NCBI UCSC ] 22: 36691115 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 20, 2024 Sep 2, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_002473.6:c.3493C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002464.1:p.Arg1165Cys missense NC_000022.11:g.36295069G>A NC_000022.10:g.36691115G>A NG_011884.2:g.97950C>T LRG_567:g.97950C>T LRG_567t1:c.3493C>T LRG_567p1:p.Arg1165Cys P35579:p.Arg1165Cys - Protein change
- R1165C
- Other names
- -
- Canonical SPDI
- NC_000022.11:36295068:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| MYH9 | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1384 | 1490 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Sep 2, 2022 | RCV000015121.38 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Dec 12, 2018 | RCV000790357.6 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 4, 2022 | RCV001092004.35 | |
| Pathogenic (1) |
no assertion criteria provided
|
May 1, 2020 | RCV001270614.3 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 29, 2020 | RCV001542710.5 |
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
Help
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 12, 2018)
|
criteria provided, single submitter
Method: research
|
MYH9-related disorder
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000891150.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
Comment:
PS4, PM2, PP1_strong, PP4, PP3
Observation 1:
Sex: male
Ethnicity/Population group: European
Observation 2:
Sex: female
Ethnicity/Population group: European
Observation 3:
Sex: male
Ethnicity/Population group: European
Observation 4:
Sex: female
Observation 5:
Sex: male
Ethnicity/Population group: European
Observation 6:
Sex: female
Ethnicity/Population group: European
|
|
|
Pathogenic
(Mar 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: unknown
Allele origin:
germline
|
Johns Hopkins Genomics, Johns Hopkins University
Accession: SCV001548525.1
First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
|
|
|
Pathogenic
(Dec 13, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002067417.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the MYH9 gene demonstrated a sequence change, c.3493C>T, in exon 27 that results in an amino acid change, p.Arg1165Cys. This sequence … (more)
DNA sequence analysis of the MYH9 gene demonstrated a sequence change, c.3493C>T, in exon 27 that results in an amino acid change, p.Arg1165Cys. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg1165Cys change has been identified in several families with thrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss (PMID: 26056797, 16098078, 10973259, 11776386, 10973259, 11776386). The p.Arg1165Cys change affects a moderately conserved amino acid residue located in a domain of the MYH9 protein that is known to be functional. The p.Arg1165Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Additionally, functional studies demonstrate that this sequence change impacts protein structure, leading to reduced function (PMID: 15339844). (less)
|
|
|
Pathogenic
(Sep 29, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 17
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761473.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Sep 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002769453.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are likely mechanisms of disease in this gene and are associated with autosomal dominant deafness 17 (MIM#603622) and macrothrombocytopaenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100) (PMID: 32545517; GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail 1 coiled coil region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple individuals or families with inherited bleeding disorders (ClinVar, PMIDs: 32100410, 24186861). Additionally, this variant has been reported in one Japanese family with a family history of thrombocytopaenia whereby sensorineural hearing loss, cataract and nephritis were also observed in some affected relatives (PMID: 26056797). It should also be noted that p.Arg1165 is one of six residues where ~70% of affected individuals have pathogenic variants (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Mar 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017680.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jul 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002243699.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844, 16162639, 30916803). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844, 16162639, 30916803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14074). This missense change has been observed in individuals with MYH9-related disorders (PMID: 10973259, 17655694, 26056797). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1165 of the MYH9 protein (p.Arg1165Cys). (less)
|
|
|
Pathogenic
(Feb 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248332.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: yes
Allele origin:
germline
|
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology
Accession: SCV002500898.2
First in ClinVar: Apr 23, 2022 Last updated: Sep 10, 2022
Comment:
Submitted to GoldVariant by Jose María Bastida and José Rivera; Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC)
|
Observation 1:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Sex: female
Observation 2:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Sex: female
Observation 3:
Clinical Features:
Macrothrombocytopenia (present)
Family history: yes
Sex: male
|
|
|
Pathogenic
(Sep 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572550.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014074). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). A different missense change at the same codon (p.Arg1165Leu) has been reported to be associated with MYH9-related disorder (ClinVar ID: VCV000038965/ PMID: 11776386). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Thrombocytopenia (present) , Increased mean platelet volume (present) , Increased mean platelet volume (present) , Unilateral renal agenesis (present) , Ureteropelvic junction obstruction (present)
|
|
|
Pathogenic
(Sep 01, 2000)
|
no assertion criteria provided
Method: literature only
|
MACROTHROMBOCYTOPENIA AND GRANULOCYTE INCLUSIONS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035378.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 30, 2018 |
Comment on evidence:
In a family diagnosed with Sebastian syndrome (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had a heterozygous 3493C-T transition in the … (more)
In a family diagnosed with Sebastian syndrome (MATINS; 155100), the May-Hegglin/Fechtner Syndrome Consortium (2000) found that affected individuals had a heterozygous 3493C-T transition in the MYH9 gene, resulting in an arg1165-to-cys (R1165C) substitution. (less)
|
|
|
Pathogenic
(May 01, 2020)
|
no assertion criteria provided
Method: research
|
Thrombocytopenia
Abnormal bleeding
Affected status: yes
Allele origin:
germline
|
Birmingham Platelet Group; University of Birmingham
Accession: SCV001450913.1
First in ClinVar: Dec 19, 2020 Last updated: Dec 19, 2020 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal dominant nonsyndromic hearing loss 17
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760486.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Pathogenic
(Dec 12, 2023)
|
no assertion criteria provided
Method: clinical testing
|
MYH9-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004732787.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The MYH9 c.3493C>T variant is predicted to result in the amino acid substitution p.Arg1165Cys. This variant has been reported to be causative for MYH9-related disorders … (more)
The MYH9 c.3493C>T variant is predicted to result in the amino acid substitution p.Arg1165Cys. This variant has been reported to be causative for MYH9-related disorders in several patients (Seri et al. 2000. PubMed ID: 10973259; Seri et al. 2003. PubMed ID: 12792306; Dong et al. 2005. PubMed ID: 16098078; Pecci et al. 2008. PubMed ID: 18059020) and is consistent with a clinical diagnosis of a MYH9-related disorder. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss
Affected status: unknown
Allele origin:
germline
|
GeneReviews
Accession: SCV000055826.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
Comment:
Associated with high risk for hearing loss and low risk for nephropathy and cataract
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
DNA sequence analysis of the MYH9 gene demonstrated a sequence change, c.3493C>T, in exon 27 that results in an amino acid change, p.Arg1165Cys. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg1165Cys change has been identified in several families with thrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss (PMID: 26056797, 16098078, 10973259, 11776386, 10973259, 11776386). The p.Arg1165Cys change affects a moderately conserved amino acid residue located in a domain of the MYH9 protein that is known to be functional. The p.Arg1165Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Additionally, functional studies demonstrate that this sequence change impacts protein structure, leading to reduced function (PMID: 15339844).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are likely mechanisms of disease in this gene and are associated with autosomal dominant deafness 17 (MIM#603622) and macrothrombocytopaenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100) (PMID: 32545517; GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail 1 coiled coil region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple individuals or families with inherited bleeding disorders (ClinVar, PMIDs: 32100410, 24186861). Additionally, this variant has been reported in one Japanese family with a family history of thrombocytopaenia whereby sensorineural hearing loss, cataract and nephritis were also observed in some affected relatives (PMID: 26056797). It should also be noted that p.Arg1165 is one of six residues where ~70% of affected individuals have pathogenic variants (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844, 16162639, 30916803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14074). This missense change has been observed in individuals with MYH9-related disorders (PMID: 10973259, 17655694, 26056797). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1165 of the MYH9 protein (p.Arg1165Cys).
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014074). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). A different missense change at the same codon (p.Arg1165Leu) has been reported to be associated with MYH9-related disorder (ClinVar ID: VCV000038965/ PMID: 11776386). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The MYH9 c.3493C>T variant is predicted to result in the amino acid substitution p.Arg1165Cys. This variant has been reported to be causative for MYH9-related disorders in several patients (Seri et al. 2000. PubMed ID: 10973259; Seri et al. 2003. PubMed ID: 12792306; Dong et al. 2005. PubMed ID: 16098078; Pecci et al. 2008. PubMed ID: 18059020) and is consistent with a clinical diagnosis of a MYH9-related disorder. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Associated with high risk for hearing loss and low risk for nephropathy and cataract
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. |
Comment:
PS4, PM2, PP1_strong, PP4, PP3
Comment:
DNA sequence analysis of the MYH9 gene demonstrated a sequence change, c.3493C>T, in exon 27 that results in an amino acid change, p.Arg1165Cys. This sequence change has not been described in population databases (gnomAD, ExAC). The p.Arg1165Cys change has been identified in several families with thrombocytopenia with or without granulocyte inclusions, nephritis, or sensorineural hearing loss (PMID: 26056797, 16098078, 10973259, 11776386, 10973259, 11776386). The p.Arg1165Cys change affects a moderately conserved amino acid residue located in a domain of the MYH9 protein that is known to be functional. The p.Arg1165Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Additionally, functional studies demonstrate that this sequence change impacts protein structure, leading to reduced function (PMID: 15339844).
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are likely mechanisms of disease in this gene and are associated with autosomal dominant deafness 17 (MIM#603622) and macrothrombocytopaenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100) (PMID: 32545517; GeneReviews). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Expressivity varies for onset and severity of sensorineural deafness, glomerular nephropathy, presenile cataract, and alterations of liver enzymes (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail 1 coiled coil region (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple individuals or families with inherited bleeding disorders (ClinVar, PMIDs: 32100410, 24186861). Additionally, this variant has been reported in one Japanese family with a family history of thrombocytopaenia whereby sensorineural hearing loss, cataract and nephritis were also observed in some affected relatives (PMID: 26056797). It should also be noted that p.Arg1165 is one of six residues where ~70% of affected individuals have pathogenic variants (GeneReviews). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH9 function (PMID: 15339844, 16162639, 30916803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 14074). This missense change has been observed in individuals with MYH9-related disorders (PMID: 10973259, 17655694, 26056797). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1165 of the MYH9 protein (p.Arg1165Cys).
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.92; 3Cnet: 0.51). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014074). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). A different missense change at the same codon (p.Arg1165Leu) has been reported to be associated with MYH9-related disorder (ClinVar ID: VCV000038965/ PMID: 11776386). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The MYH9 c.3493C>T variant is predicted to result in the amino acid substitution p.Arg1165Cys. This variant has been reported to be causative for MYH9-related disorders in several patients (Seri et al. 2000. PubMed ID: 10973259; Seri et al. 2003. PubMed ID: 12792306; Dong et al. 2005. PubMed ID: 16098078; Pecci et al. 2008. PubMed ID: 18059020) and is consistent with a clinical diagnosis of a MYH9-related disorder. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Comment:
Associated with high risk for hearing loss and low risk for nephropathy and cataract
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| MYH9-Related Disease. | Adam MP | - | 2021 | PMID: 20301740 |
| Linking the Landscape of MYH9-Related Diseases to the Molecular Mechanisms that Control Non-Muscle Myosin II-A Function in Cells. | Asensio-Juárez G | Cells | 2020 | PMID: 32545517 |
| Genetic screening of children with suspected inherited bleeding disorders. | Andersson NG | Haemophilia : the official journal of the World Federation of Hemophilia | 2020 | PMID: 32100410 |
| MYH9-related disease mutations cause abnormal red blood cell morphology through increased myosin-actin binding at the membrane. | Smith AS | American journal of hematology | 2019 | PMID: 30916803 |
| Genotype-phenotype Correlation of the p.R1165C Mutation in the MYH9 Disorder: Report of a Japanese Pedigree. | Okano S | Journal of pediatric hematology/oncology | 2015 | PMID: 26056797 |
| MYH9-related disease: a novel prognostic model to predict the clinical evolution of the disease based on genotype-phenotype correlations. | Pecci A | Human mutation | 2014 | PMID: 24186861 |
| MYH9-related disorders: report on a patient of Greek origin presenting with macroscopic hematuria and presenile cataract, caused by an R1165C mutation. | Economou M | Journal of pediatric hematology/oncology | 2012 | PMID: 22627578 |
| Recent advances in the understanding and management of MYH9-related inherited thrombocytopenias. | Balduini CL | British journal of haematology | 2011 | PMID: 21542825 |
| Position of nonmuscle myosin heavy chain IIA (NMMHC-IIA) mutations predicts the natural history of MYH9-related disease. | Pecci A | Human mutation | 2008 | PMID: 18059020 |
| Perioperative management of MYH9 hereditary macrothrombocytopenia (Fechtner syndrome). | Selleng K | European journal of haematology | 2007 | PMID: 17655694 |
| Pathogenetic mechanisms of hematological abnormalities of patients with MYH9 mutations. | Pecci A | Human molecular genetics | 2005 | PMID: 16162639 |
| Genotype-phenotype correlation in MYH9-related thrombocytopenia. | Dong F | British journal of haematology | 2005 | PMID: 16098078 |
| Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly. | Franke JD | Blood | 2005 | PMID: 15339844 |
| Immunofluorescence analysis of neutrophil nonmuscle myosin heavy chain-A in MYH9 disorders: association of subcellular localization with MYH9 mutations. | Kunishima S | Laboratory investigation; a journal of technical methods and pathology | 2003 | PMID: 12533692 |
| Identification of six novel MYH9 mutations and genotype-phenotype relationships in autosomal dominant macrothrombocytopenia with leukocyte inclusions. | Kunishima S | Journal of human genetics | 2001 | PMID: 11776386 |
| 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 |
| click to load more click to collapse | ||||
Text-mined citations for rs80338829 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 10, 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.