NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 4, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001092004.35

Allele description [Variation Report for NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys)]

NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys)

Gene:

MYH9:myosin heavy chain 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q12.3

Genomic location:

Preferred name:

NM_002473.6(MYH9):c.3493C>T (p.Arg1165Cys)

HGVS:

NC_000022.11:g.36295069G>A
NG_011884.2:g.97950C>T
NM_002473.6:c.3493C>TMANE SELECT
NP_002464.1:p.Arg1165Cys
NP_002464.1:p.Arg1165Cys
LRG_567t1:c.3493C>T
LRG_567:g.97950C>T
LRG_567p1:p.Arg1165Cys
NC_000022.10:g.36691115G>A
NM_002473.4:c.3493C>T
NM_002473.5:c.3493C>T
P35579:p.Arg1165Cys

Protein change:

R1165C; ARG1165CYS

Links:

UniProtKB: P35579#VAR_010795; OMIM: 160775.0003; dbSNP: rs80338829

NCBI 1000 Genomes Browser:

rs80338829

Molecular consequence:

NM_002473.6:c.3493C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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PREDICTED: Taeniopygia guttata probable G-protein coupled receptor 83 (LOC100228...
PREDICTED: Taeniopygia guttata probable G-protein coupled receptor 83 (LOC100228113), transcript variant X1, mRNA
gi|2043870722|ref|XM_041716137.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001248332	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2020)	germline	clinical testing	Citation Link,
SCV002017680	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002067417	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 13, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002243699	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 4, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15339844, 16162639, 30916803, 10973259, 17655694, 26056797, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Rod mutations associated with MYH9-related disorders disrupt nonmuscle myosin-IIA assembly.

Franke JD, Dong F, Rickoll WL, Kelley MJ, Kiehart DP.

Blood. 2005 Jan 1;105(1):161-9. Epub 2004 Aug 31.

PubMed [citation]

PMID:: 15339844

See all PubMed Citations (8)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001248332.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002017680.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV002067417.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243699.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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