Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV000116960 | SCV000151075 | uncertain significance | not provided | 2014-03-18 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000116960 | SCV001155870 | likely pathogenic | not provided | 2018-11-01 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Applied Genomics, |
RCV000116960 | SCV001447927 | likely pathogenic | not provided | 2020-10-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV002528212 | SCV003441327 | likely pathogenic | Kleefstra syndrome 1 | 2022-02-01 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 809 of the EHMT1 protein (p.Pro809Leu). 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. Experimental studies have shown that this missense change affects EHMT1 function (PMID: 28057753). 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: 128978). This missense change has been observed in individual(s) with clinical features of Kleefstra syndrome (PMID: 28057753, 29276005, 31785789, 33767182). In at least one individual the variant was observed to be de novo. |
Genetics and Molecular Pathology, |
RCV002528212 | SCV004175681 | pathogenic | Kleefstra syndrome 1 | 2022-09-05 | criteria provided, single submitter | clinical testing | The EHMT1 c.2426C>T variant is classified as PATHOGENIC (PS2, PS3, PS4, PP3) The EHMT1 c.2426C>T variant is a single nucleotide change in exon 16/27 of the EHMT1 gene, which is predicted to change the amino acid proline at position 809 in the protein to leucine. This variant has been identified as a de novo variant in this patient, although was detected in a very small proportion of reads in the mother (2 of 72, ~3%) (PS2). It has also been reported as de novo in an individual with Kleefstra syndrome in the literature, along with another unrelated Kleefstra syndrome case (PMID: 28057753; PS4). This variant is absent from population databases (PM2). Functional studies have demonstrated the variant leads to protein misfolding and aberrant target recognition via disrupted histone mark binding (PS3). Computational predictions support a deleterious effect on the gene or gene product (PP3). This variant has been reported in dbSNP (rs587780332) and has been reported as likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 128978), and damaging for Kleefstra syndrome in HGMD (CM172582). |