Submissions for variant NM_002473.6(MYH9):c.5797C>T (p.Arg1933Ter)

dbSNP: rs80338835

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000790363	SCV000891156	pathogenic	MYH9-related disorder	2018-12-12	criteria provided, single submitter	research	PS4, PM2, PM1, PP4
CeGaT Center for Human Genetics Tuebingen	RCV001092002	SCV001248330	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001092002	SCV001447399	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001092002	SCV001781766	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Identified in more than 40 individuals from over 20 families with variable clinical findings of MYH9-related disease (Sung et al., 2014; Ali et al., 2016; Pecci et al,. 2014; Pecci et al., 2008; Savoia et al., 2010); Published functional studies demonstrate that R1933X does not form organized fibrillar structures with type I collagen and reduces megakaryocyte cell migration (Pecci et al., 2011; Franke et al., 2005); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 28 amino acids are lost; other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10739770, 31064749, 24186861, 23207509, 15339844, 21833445, 19572073, 20694274, 21429376, 10973259, 28880435, 11590545, 10973260, 19954613, 23759689, 27291889, 26226608, 30993846, 33855781, 28983057, 33217855)
Revvity Omics, Revvity	RCV001092002	SCV002017679	pathogenic	not provided	2021-07-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092002	SCV002113290	pathogenic	not provided	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1933*) in the MYH9 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 28 amino acid(s) of the MYH9 protein. This variant is present in population databases (rs80338835, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with MYH9-related disorders (PMID: 10739770, 10973259, 23207509). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14072). For these reasons, this variant has been classified as Pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000015116	SCV002500899	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000015116	SCV002557804	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative or loss of function are potential mechanisms of disease in this gene and are associated with deafness, autosomal dominant 17 (MIM#603622), and macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss (MIM#155100). Although the disease mechanism is not well understood, several hypotheses have been proposed including variants that are partially deficient but not complete loss of function, variants that cause various degrees of protein aggregation with deleterious effect, and variants that impair the function of other myosins when copolymerised (PMID: 32545517). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity with regard to age of onset, severity of sensorineural deafness, and the presence or absence of glomerular nephropathy, presenile cataract, and alterations of liver enzymes (PMID: 20301740). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0702 - Other downstream truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in several families with thrombocytopenia (PMIDs: 29090586, 11159552) and classified as pathogenic by five clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Genetics and Molecular Pathology, SA Pathology	RCV000015116	SCV002761723	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2021-12-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001092002	SCV004227693	pathogenic	not provided	2023-06-14	criteria provided, single submitter	clinical testing	PP1_strong, PM2_supporting, PS3, PS4, PVS1_strong
Suma Genomics	RCV000015116	SCV004244383	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		criteria provided, single submitter	clinical testing
OMIM	RCV000015116	SCV000035373	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2001-11-01	no assertion criteria provided	literature only
GeneReviews	RCV000015116	SCV000055833	not provided	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		no assertion provided	literature only	Thrombocytopenia usually remains only disease manifestation throughout life
Birmingham Platelet Group; University of Birmingham	RCV001270545	SCV001450844	pathogenic	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research