Submissions for variant NM_024757.5(EHMT1):c.3259-1G>A

dbSNP: rs1554897763

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578826	SCV000681352	pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing	The c.3259-1 G>A variant in the EHMT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice acceptor site in intron 22. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.3259-1 G>A variant is not observed in large population cohorts (Lek et al., 2016).
Invitae	RCV002530372	SCV003231817	likely pathogenic	Kleefstra syndrome 1	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 22 of the EHMT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in EHMT1 are known to be pathogenic (PMID: 16826528, 19264732). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EHMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 489352). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.