Submissions for variant NM_024757.5(EHMT1):c.3725_3726del (p.Tyr1242fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471434	SCV002768080	uncertain significance	Kleefstra syndrome 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Kleefstra syndrome 1 (MIM#610253). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0208 - Variant is predicted to result in an elongated protein. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0601 - Variant is located in the well-established functional SET domain (NCBI), and the frameshift of the C-terminal will result in the substitution of multiple predicted active sites as well as amino acids involved in binding and catalytic activity (NCBI). In addition, this variant alters a region predicted to be involved in interaction with histone H3 (Uniprot). (SP) 0705 - No comparable elongation variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Molecular Genetics, Royal Melbourne Hospital	RCV002471434	SCV004812550	uncertain significance	Kleefstra syndrome 1	2022-05-05	criteria provided, single submitter	clinical testing	This sequence change is a deletion of 2 bp in exon 27 (of 27) of EHMT1 that is predicted to alter the amino acid sequence at position 1242 and extend the protein by 19 amino acids, p.(Tyr1242Trpfs*76). The role of the altered region of the protein and the effects of protein elongation is unknown. The variant is absent in a large population cohort (gnomAD v2.1 and v3.1), and has not been reported in the relevant medical literature and databases. The variant is assumed de novo in an individual with a complex neurodevelopmental disorder (Royal Melbourne Hospital). The methylation signature in this individual does not resemble the methylation signature seen in Kleefstra syndrome (EpiSign, London Health Sciences Centre). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PVS1_Moderate, PM6, PM2_Supporting.