Submissions for variant NM_002473.6(MYH9):c.2105G>A (p.Arg702His)

gnomAD frequency: 0.00001  dbSNP: rs80338827

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851738	SCV000899591	likely pathogenic	MYH9-related disorder	2019-02-01	criteria provided, single submitter	research
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000015132	SCV001367796	likely pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP4.
DASA	RCV000851738	SCV002107101	pathogenic	MYH9-related disorder	2022-03-05	criteria provided, single submitter	clinical testing	The c.2105G>A;p.(Arg702His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 14081; PMID: 31064749; PMID: 11935325; PMID: 11590545) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Myosin_head) - PM1. This variant is not present in population databases (rs80338827- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant co-segregated with disease in multiple affected family members (PMID: 11935325) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851865	SCV002240952	pathogenic	not provided	2024-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 702 of the MYH9 protein (p.Arg702His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MYH9-related disease (PMID: 11590545, 11935325, 26387855). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 14081). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYH9 protein function. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001851865	SCV002563725	pathogenic	not provided	2018-07-01	criteria provided, single submitter	clinical testing
3billion	RCV000015132	SCV003841968	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). 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: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014081). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24186861). Different missense changes at the same codon (p.Arg702Cys, p.Arg702Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000014078, VCV000627035). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001851865	SCV005325113	pathogenic	not provided	2024-03-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31064749, 23207509, 16098078, 26226608, 37201161, 31328266, 34383333, 24186861, 37752057, 25077172, 30103613, 22558294, 24165359, 37733142, 23223919, 11590545, 20200500, 26387855, 30916803, 17241369, 35530141, 11935325, 32980210)
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000015132	SCV005374381	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2024-09-22	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001851865	SCV005413405	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	PP1_strong, PP2, PP3, PP4, PM1, PM5, PM6, PS4_moderate
Center for Statistical Genetics, Columbia University	RCV000015132	SCV005415637	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2024-11-08	criteria provided, single submitter	research
OMIM	RCV000015132	SCV000035389	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2002-02-01	no assertion criteria provided	literature only
GeneReviews	RCV000015132	SCV000055823	not provided	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		no assertion provided	literature only	Associated with most severe phenotype