Submissions for variant NM_002473.6(MYH9):c.287C>T (p.Ser96Leu)

dbSNP: rs121913657

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000790352	SCV000891145	pathogenic	MYH9-related disorder	2018-12-12	criteria provided, single submitter	research	PS4, PM1, PM2, PP4, PP3
Molecular Biology Laboratory, Fundació Puigvert	RCV000015138	SCV001425108	likely pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2020-02-01	criteria provided, single submitter	research
GeneDx	RCV001537286	SCV001754151	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23940247, 30214762, 16098078, 32447941, 31064749, 35125114, 35537118, 24186861, 23409987, 11752022, 32520844, 29782633, 26226608, 29801666, 29797310, 28780565, 29199357, 29090586, 18059020, 21210153, 16969870, 12533692, 28960434, 20174760, 24165359, 25077172, 29143464, 29532554, 22273764, 30471777, 30720677, 30431218, 31562665, 32581362, 33855781, 28983057, 32604935, 35295078)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000015138	SCV002051452	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2021-12-03	criteria provided, single submitter	clinical testing	Variant summary: MYH9 c.287C>T (p.Ser96Leu) results in a non-conservative amino acid change located in the Myosin head, motor domain (IPR001609) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251418 control chromosomes (gnomAD). c.287C>T has been reported in the literature in multiple individuals affected with Macrothrombocytopenia And Granulocyte Inclusions With Or Without Nephritis Or Sensorineural Hearing Loss (example: Arrondel_2002, Pecci_2008, Furlano_2019, Park_2020). The variant is also documented to have arisen de novo in affected patients from two unrelated families with no history of disease (Arrondel_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the mutant protein on cellular function, where enriched ex vivo Natural Killer cells from a patient with the variant had diminished cytotoxic abilities in vitro (Sanborn_2011). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and three as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000015138	SCV002500900	likely 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	RCV000015138	SCV002767204	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from a serine to a leucine (exon 2). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (myosin motor domain; PDB, NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in multiple individuals with MYH9-related disorder or macrothrombocytopenia (ClinVar, PMID:12533692, PMID:29782633, PMID:29532554, PMID:26226608). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1001 - Strong functional evidence supporting abnormal protein localization within patient cells (PMID:12533692). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV001537286	SCV003444485	pathogenic	not provided	2022-08-20	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with MYH9-related conditions (PMID: 11752022, 24186861). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MYH9 function (PMID: 22123909). 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: 14083). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 96 of the MYH9 protein (p.Ser96Leu).
CeGaT Center for Human Genetics Tuebingen	RCV001537286	SCV004147813	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	MYH9: PM2, PP4:Moderate, PS2:Moderate, PS4:Moderate, PP3, PS3:Supporting
OMIM	RCV000015138	SCV000035395	pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2006-10-15	no assertion criteria provided	literature only
GeneReviews	RCV000015138	SCV000086884	not provided	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000477821	SCV000536932	pathogenic	Autosomal dominant nonsyndromic hearing loss 17	2016-05-28	no assertion criteria provided	research