Submissions for variant NM_024757.5(EHMT1):c.2018+1G>T

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004785027	SCV005397457	likely pathogenic	Kleefstra syndrome 1	2022-05-25	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (G>T) at the +1 canonical splice site of intron 12 in the EHMT1 gene. Disruption of this canonical splice site is expected to generate a non-functiol allele through either the expression of a truncated protein or a loss of EHMT1 expression due to nonsense mediated decay. This variant is absent from online datasets of clinically annotated variants (ClinVar) and has not been observed in individuals with EHMT1-related disease in the published literature, to our knowledge. However, a similar variant at this position (EHMT1 c.2018+1G>C) was observed in an individual with Kleefstra syndrome (PMID: 33288889). This variant is absent from control population datasets (gnomAD database, 0 of 250,000 alleles). Multiple bioinformatic tools predict that this G to T substitution will disrupt the proper splicing of EHMT1, and G at this position is strongly conserved across the vertebrate species examined. Studies examining the functiol consequence of this variant have not been published, to our knowledge. Given this information, we consider this a likely pathogenic variant. ACMG Criteria: PM2, PVS1