Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000210678 | SCV000262933 | likely pathogenic | Inborn genetic diseases | 2012-11-29 | criteria provided, single submitter | clinical testing | The p.P436L alteration (also known as c.1307C>T) is located in exon 8 of the EHMT1 gene. This alteration results from a C to T substitution at nucleotide position 1307. The proline at codon 436 is replaced by leucine, an amino acid with somewhat dissimilar properties. This amino acid position is highly conserved in available vertebrate species. The alteration is predicted to be possibly damaging by PolyPhen and deleterious by SIFT in silico prediction tools. Based on the available evidence to date, this alteration is likely deleterious. |
| Invitae | RCV001853375 | SCV002301322 | uncertain significance | Kleefstra syndrome 1 | 2021-02-28 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with EHMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 225043). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 436 of the EHMT1 protein (p.Pro436Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. |
| New York Genome Center | RCV001853375 | SCV002506804 | uncertain significance | Kleefstra syndrome 1 | 2021-06-11 | criteria provided, single submitter | clinical testing | The heterozygous c.1307C>T (p.Pro436Leu) missense variant identified in the EHMT1 gene has not been reported in affected individuals in the literature to the best of our knowledge. The variant has been reported in ClinVar by one laboratory as Likely Pathogenic [Variation ID: 225043, one submission dated 2012]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue. In silico tools provide conflicting predictions about potential pathogenicity of this variant (CADD score = 23.3, REVEL score = 0.207). Based on the available evidence, the heterozygous c.1307C>T (p.Pro436Leu) missense variant identified in the EHMT1 gene is reported as a variant of uncertain significance. |