Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000150836 | SCV000198378 | likely pathogenic | Costello syndrome | 2013-08-22 | criteria provided, single submitter | clinical testing | The Gly12Glu variant in HRAS has been reported in one individual with a neonatal presentation of Costello syndrome (Kerr 2006). Several other DNA variants affec ting codon 12 of HRAS are commonly observed in patients with Costello syndrome ( Niihori 2011). In addition this variant has not been identified in large populat ion studies. Glycine (Gly) at this position is highly conserved across evolution arily distinct species, and computational analyses (biochemical amino acid prope rties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein. In summary, this variant is likely pathogenic, though additional studie s are required to fully establish its clinical significance. |
Gene |
RCV000255809 | SCV000321770 | pathogenic | not provided | 2017-05-31 | criteria provided, single submitter | clinical testing | The c.35_36delGCinsAA variant resulting in a G12E missense variant in the HRAS gene has been reported previously as de novo and in association with Costello syndrome (Weaver et al., 2014). The c.35_36delGCinsAA was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variants in these populations. The G12E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants in this same residue (G12S, G12C, G12A, G12V, G12D) have been reported in the Human Gene Mutation Database in association with Costello syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein." |