rs80338829

chr22-36295069-G-A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_002473.6(MYH9):c.3493C>T(p.Arg1165Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1165L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 6.69

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 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-36295068-C-A is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, MYH9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 22-36295069-G-A is Pathogenic according to our data. Variant chr22-36295069-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36295069-G-A is described in Lovd as [Pathogenic]. Variant chr22-36295069-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.3493C>T	p.Arg1165Cys	missense_variant	27/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.3493C>T	p.Arg1165Cys	missense_variant	27/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.3556C>T	p.Arg1186Cys	missense_variant	28/42
MYH9	ENST00000691109.1	n.3788C>T		non_coding_transcript_exon_variant	21/35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:5 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
not provided, no classification provided	literature only	GeneReviews	-	Associated with high risk for hearing loss and low risk for nephropathy and cataract -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Sep 02, 2022	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 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2000	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2019	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 04, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 14, 2019	- -

Autosomal dominant nonsyndromic hearing loss 17 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 29, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

MYH9-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Dec 12, 2018	PS4, PM2, PP1_strong, PP4, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2023	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. -

Thrombocytopenia;C1458140:Abnormal bleeding Pathogenic:1

Pathogenic, no assertion criteria provided

research

Birmingham Platelet Group; University of Birmingham

May 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.76		Loss of MoRF binding (P = 0.0272);
MVP		0.94
MPC		1.7
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.72
gMVP		0.68

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: rs80338829; hg19: chr22-36691115;