Submissions for variant NM_002834.5(PTPN11):c.217A>C (p.Thr73Pro)

dbSNP: rs397507513

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000033474	SCV000057379	pathogenic	not provided	2013-02-07	criteria provided, single submitter	clinical testing	The T73P mutation has not been reported as a disease-causing mutation or as a benign polymorphism, to our knowledge. A different missense mutation at this codon (T73I) has been reported previously in association with Noonan syndrome and in a single patient reported to have Noonan-like/multiple giant cell lesion syndrome (NS/MGCLS) (Tartaglia et al., 2002; Bufalino et al., 2010). Additionally, T73I is the most common mutation found in infants with Noonan syndrome / Myeloproliferative disease (MPD), having been identified in 8 out of 19 children studied (Kratz et al., 2005). The T73P missense change is a non-conservative amino acid substitution that affects a highly evolutionarily conserved residue within a known functional domain of the PTPN11 protein. As another missense mutation at this codon has also been published in association with PTPN11-related disorders, T73P is interpreted as a disease-causing mutation.The variant is found in NOONAN panel(s).
AiLife Diagnostics, AiLife Diagnostics	RCV000033474	SCV002502817	likely pathogenic	not provided	2021-12-08	criteria provided, single submitter	clinical testing
3billion	RCV003152671	SCV003841675	pathogenic	Noonan syndrome 1	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000040501) and different missense changes at the same codon (p.Thr73Ile, p.Thr73Leu / ClinVar ID: VCV000013334, VCV000044604) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654180	SCV004534620	likely pathogenic	RASopathy	2023-03-20	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Thr73Ile amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 14644997, 15240615, 15928039, 17020470, 17339163). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 40501). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 73 of the PTPN11 protein (p.Thr73Pro).