Submissions for variant NM_002473.6(MYH9):c.2680G>A (p.Glu894Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003225632	SCV003921826	likely pathogenic	Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are likely 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; GeneReviews, 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/absence of glomerular nephropathy, presenile cataract, and alterations of liver enzymes (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated myosin tail domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with MYH9-related disease, one of them de novo, with variable phenotypes including kidney disease, thrombocytopenia, and cataracts (PMIDs: 24165359, 25077172, 31384440). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. This variant is not maternally inherited (by duo analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Mayo Clinic Laboratories, Mayo Clinic	RCV004790509	SCV005413404	likely pathogenic	not provided	2024-05-21	criteria provided, single submitter	clinical testing	PP2, PP3, PM2_moderate, PS4_moderate