Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV001577287 | SCV001471242 | uncertain significance | not provided | 2020-02-05 | criteria provided, single submitter | clinical testing | The PTPN11 c.1402A>G; p.Thr468Ala variant (rs886039711), to our knowledge, is not reported in the medical literature or gene-specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 468 is highly conserved, it occurs in the protein tyrosine phosphatase domain in the catalytic site consensus sequence (Digilio 2002), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, other amino acid substitutions at this codon (p.Thr468Met, p.Thr468Pro) have been reported in individuals with LEOPARD syndrome, also called Noonan syndrome with multiple lentigines, and are considered disease-causing (Digilio 2002, Martinelli 2008, Motegi 2015). Functional studies of the p.Thr468Ala variant indicate it has slightly decreased catalytic activity and increased affinity for phosphotyrosine peptides, although other substitutions at the same position exhibit more significantly decreased catalytic activity (Martinelli 2008). However, given the lack of clinical data, the significance of the p.Thr468Ala variant is uncertain at this time. References: Digilio MC et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002 Aug;71(2):389-94. Martinelli S et al. Diverse driving forces underlie the invariant occurrence of the T42A, E139D, I282V and T468M SHP2 amino acid substitutions causing Noonan and LEOPARD syndromes. Hum Mol Genet. 2008 Jul 1;17(13):2018-29. Motegi S et al. Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation. Acta Derm Venereol. 2015 Nov;95(8):978-84. |
| Gene |
RCV001577287 | SCV001804639 | likely pathogenic | not provided | 2020-01-06 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge |