VCV000164439.30 - ClinVar

NM_002473.6(MYH9):c.4225G>A (p.Asp1409Asn)

Germline

Classification

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(5); Benign(1); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002473.6(MYH9):c.4225G>A (p.Asp1409Asn)

Variation ID: 164439 Accession: VCV000164439.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q12.3 22: 36292105 (GRCh38) [ NCBI UCSC ] 22: 36688151 (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	Dec 6, 2016	Nov 24, 2024	Dec 27, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002473.6:c.4225G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002464.1:p.Asp1409Asn	missense
NM_002473.5:c.4225G>A
NC_000022.11:g.36292105C>T
NC_000022.10:g.36688151C>T
NG_011884.2:g.100914G>A
LRG_567:g.100914G>A

... more HGVS ... less HGVS

Protein change

D1409N

Other names

Canonical SPDI

NC_000022.11:36292104:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD) 0.00025

Exome Aggregation Consortium (ExAC) 0.00026

The Genome Aggregation Database (gnomAD), exomes 0.00030

Trans-Omics for Precision Medicine (TOPMed) 0.00036

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

Links

ClinGen: CA177099 dbSNP: rs34292387 VarSome

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
Gene	OMIM	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	1392	1498

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 16, 2013	RCV000151333.9
Autosomal dominant nonsyndromic hearing loss 17	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000386272.5
MYH9-related disorder	Benign (2)	criteria provided, single submitter	Jan 13, 2018	RCV000291994.6
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Dec 27, 2023	RCV000724779.25
Meniere disease	Uncertain significance (1)	no assertion criteria provided	Jun 3, 2024	RCV004567172.1

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.
Uncertain significance (Jul 31, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000229423.5 First in ClinVar: Jun 29, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH9 Number of individuals with the variant: 2 Sex: mixed
Uncertain significance (Apr 16, 2013)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000199304.4 First in ClinVar: Jan 30, 2015 Last updated: Apr 09, 2018	Comment: Variant classified as Uncertain Significance - Favor Benign. The Asp1409Asn vari ant in MYH9 has not been reported in the literature nor previously identified by … (more) Variant classified as Uncertain Significance - Favor Benign. The Asp1409Asn vari ant in MYH9 has not been reported in the literature nor previously identified by our laboratory. The variant has been seen in 0.07% (6/8600) of European America n chromosomes in a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; rs142486910). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. In summary, a conclus ive interpretation of the impact of this variant cannot be determined but we wou ld lean towards a more likely benign role given the presence of the variant in t he general population which is less consistent with the dominant association of mutations in this gene. (less) Number of individuals with the variant: 2
Uncertain significance (Apr 12, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618042.3 First in ClinVar: Dec 19, 2017 Last updated: Apr 30, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign with … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign with regards to MYH9-related hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 25949529) (less)
Likely benign (Dec 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002178150.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024
Uncertain significance (Nov 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005410245.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (2) PubMed: 25949529‚ 29090586 Comment: BS1_moderate Number of individuals with the variant: 1
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	MYH9-related disorder Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000438363.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Autosomal dominant nonsyndromic hearing loss 17 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000438362.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Likely benign (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004147798.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: MYH9: BS1 Number of individuals with the variant: 1
Uncertain significance (Jun 03, 2024)	no assertion criteria provided Method: research	Meniere disease Affected status: yes Allele origin: germline	Center for Computational Biology & Bioinformatics, University of California, San Diego Accession: SCV005050105.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Jul 22, 2024)	no assertion criteria provided Method: clinical testing	MYH9-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005346509.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The MYH9 c.4225G>A variant is predicted to result in the amino acid substitution p.Asp1409Asn. This variant was reported in an individual with a heritable bleeding … (more) The MYH9 c.4225G>A variant is predicted to result in the amino acid substitution p.Asp1409Asn. This variant was reported in an individual with a heritable bleeding and platelet disorder (Table 3. Westbury et al. 2015. PubMed ID: 25949529). This variant is reported in 0.049% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

Comment:

Variant classified as Uncertain Significance - Favor Benign. The Asp1409Asn vari ant in MYH9 has not been reported in the literature nor previously identified by our laboratory. The variant has been seen in 0.07% (6/8600) of European America n chromosomes in a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; rs142486910). Computational analyses (biochemical a mino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provi de strong support for or against an impact to the protein. In summary, a conclus ive interpretation of the impact of this variant cannot be determined but we wou ld lean towards a more likely benign role given the presence of the variant in t he general population which is less consistent with the dominant association of mutations in this gene.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as pathogenic or benign with regards to MYH9-related hearing loss to our knowledge; This variant is associated with the following publications: (PMID: 25949529)

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The MYH9 c.4225G>A variant is predicted to result in the amino acid substitution p.Asp1409Asn. This variant was reported in an individual with a heritable bleeding and platelet disorder (Table 3. Westbury et al. 2015. PubMed ID: 25949529). This variant is reported in 0.049% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be a primary cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnosis and treatment of MYH9-RD in an Australasian cohort with thrombocytopenia.	Rabbolini DJ	Platelets	2018	PMID: 29090586
Human phenotype ontology annotation and cluster analysis to unravel genetic defects in 707 cases with unexplained bleeding and platelet disorders.	Westbury SK	Genome medicine	2015	PMID: 25949529
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MYH9	-	-	-	-

Text-mined citations for rs34292387 ...

These 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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002473.6(MYH9):c.4225G>A (p.Asp1409Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34292387 ...