rs80338826

Positions:

• chr22-36305985-G-A
• chr22-36305985-G-T

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.2104C>T​(p.Arg702Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 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. R702H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MYH9 NM_002473.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 8.03

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 chr22-36305984-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MYH9. . Gene score misZ 3.473 (greater than the threshold 3.09). Trascript score misZ 6.1231 (greater than threshold 3.09). GenCC has associacion of gene with May-Hegglin anomaly, autosomal dominant nonsyndromic hearing loss, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, autosomal dominant nonsyndromic hearing loss 17.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 22-36305985-G-A is Pathogenic according to our data. Variant chr22-36305985-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-36305985-G-A is described in Lovd as [Pathogenic]. Variant chr22-36305985-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYH9	NM_002473.6	c.2104C>T	p.Arg702Cys	missense_variant	17/41	ENST00000216181.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYH9	ENST00000216181.11	c.2104C>T	p.Arg702Cys	missense_variant	17/41	1	NM_002473.6	P1
MYH9	ENST00000685801.1	c.2167C>T	p.Arg723Cys	missense_variant	18/42
MYH9	ENST00000687922.1	n.440C>T		non_coding_transcript_exon_variant	3/3
MYH9	ENST00000691109.1	n.2399C>T		non_coding_transcript_exon_variant	11/35

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461158 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726898

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2003	- -
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: 0.88; 3Cnet: 0.73). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). Different missense changes at the same codon (p.Arg702His, p.Arg702Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014081 , VCV000627035). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	Associated with most severe phenotype -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Mar 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 16, 2022	The MYH9 c.2104C>T variant is a single nucleotide change in exon 17/41 of the MYH9 gene, which is predicted to change the amino acid arginine at position 702 in the protein to cysteine. This variant occurs in a conserved amino acid residue in the globular-head domain of the myosin heavy chain IIA protein (PMID:11590545) (PM1). This variant is absent from population databases (PM2). The variant has been reported in several individuals and is associated with MYH9-related syndromes, including May-Hegglin anomaly (MHA) and Fechtner Syndrome (FTNS) (PMID:11590545; 24186861; 11935325) Heath et al. (PMID:11590545) reported this mutation in 6 of 20 families with Fechtner syndrome (PS4). Computational predictions support a deleterious effect on the gene or gene product (PP3). Studies of mice heterozygous for this mutation showed macrothrombocytopenia, impaired proplatelet formation, albuminuria, glomerulosclerosis, and sensory hearing loss (PMID:21908426; 23976996) (PS3). This variant is a novel missense change at an amino acid residue where a different missense change has been seen before (c.2104C>A; p. Arg702Ser) (PM4). This missense change has been observed in individuals with clinical features of MYH9-related disorders (PMID:10973259). In at least one individual the variant was observed to be de novo (PM6). The variant has been reported in dbSNP (rs80338826). The variant has been reported in ClinVar database as pathogenic (Variation ID:14078) and in the HGMD database (CM002370 as a disease causing variant with the phenotype of Fechtner syndrome. -

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2017	The R702C variant in the MYH9 gene has been reported previously in association with MYH9-related disorder, including as an apparently de novo variant in one individual (Seri et al., 2000; Heath et al., 2001; Seri et al., 2003). The R702C variant is not observed in large population cohorts (Lek et al., 2016). The R702C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and is within the myosin motor domain. Studies of mice heterozgyous for R702C show macrothrombocytopenia, impaired proplatelet formation, and the mice displayed albuminuria, glomerulosclerosis, and sensory hearing loss (Zhang et al., 2012; Suzuki et al., 2013). We interpret R702C as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2022	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg702 amino acid residue in MYH9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11590545, 11935325, 26387855). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt MYH9 protein function. ClinVar contains an entry for this variant (Variation ID: 14078). This missense change has been observed in individual(s) with clinical features of MYH9-related disorders (PMID: 10973259). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 702 of the MYH9 protein (p.Arg702Cys). -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Autosomal dominant nonsyndromic hearing loss 17 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 26, 2021

- -

Autosomal dominant nonsyndromic hearing loss 17;C5200934:Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

MYH9-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Dec 12, 2018

PS4, PS3, PM2, PP4, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	4.2	H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.046	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.97		Loss of MoRF binding (P = 0.0377);
MVP		0.99
MPC		2.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.94

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: rs80338826; hg19: chr22-36702031; COSMIC: COSV53383230; COSMIC: COSV53383230;