Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001376854 | SCV001574040 | likely pathogenic | Drash syndrome; Frasier syndrome; Wilms tumor 1; 11p partial monosomy syndrome | 2017-05-28 | criteria provided, single submitter | clinical testing | 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. 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. A different missense substitution at this codon (p.Asp464Asn) has been determined to be pathogenic (PMID: 8810912, 5665984, 1655284, 20442690, 22876585, 24379226). This suggests that the aspartic acid residue is critical for WT1 protein function and that other missense substitutions at this position may also be pathogenic. This variant has been reported in two individuals affected with WT1-related conditions (PMID: 1655284, 24402088), and was found to be de novo in one of them (PMID: 1655284). This variant is also known as p.Asp396Gly in the literature. ClinVar contains an entry for this variant (Variation ID: 3489). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with glycine at codon 464 of the WT1 protein (p.Asp464Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. |
| OMIM | RCV000003660 | SCV000023823 | pathogenic | Drash syndrome | 1991-10-18 | no assertion criteria provided | literature only |