Submissions for variant NM_002834.5(PTPN11):c.853T>G (p.Phe285Val)

dbSNP: rs397507531

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027842	SCV001190462	likely pathogenic	Noonan syndrome 1; Metachondromatosis; LEOPARD syndrome 1	2019-10-24	criteria provided, single submitter	clinical testing	PTPN11 NM_002834.4 exon 7 p.Phe285Val (c.853T>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, other variants at the same amino acid residue (Phe285Cys, Phe285Ile, Phe285Leu, Phe285Ser) have also been reported in association with disease, further supporting that this region has significance (Tartilglia 2002 PMID:11992261, Tartiglia 2006 PMID:16358218, Ferrero 2008 PMID:18678287, Hakami 2016 PMID:26918529). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV002508779	SCV002818247	likely pathogenic	not provided	2022-12-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002508779	SCV003818014	uncertain significance	not provided	2019-03-22	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224796	SCV003920891	likely pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1	2021-03-30	criteria provided, single submitter	clinical testing	PTPN11 NM_002834.4 exon 7 p.Phe285Val (c.853T>G): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, other variants at the same amino acid residue (Phe285Cys, Phe285Ile, Phe285Leu, Phe285Ser) have also been reported in association with disease, further supporting that this region has significance (Tartilglia 2002 PMID:11992261, Tartiglia 2006 PMID:16358218, Ferrero 2008 PMID:18678287, Hakami 2016 PMID:26918529). In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004532489	SCV004113322	likely pathogenic	PTPN11-related disorder	2023-05-31	criteria provided, single submitter	clinical testing	The PTPN11 c.853T>G variant is predicted to result in the amino acid substitution p.Phe285Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has conflicting interpretations of pathogenicity in ClinVar of likely pathogenic and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/40527/). Alternate missense variants affecting this residue (p.Phe285Ile, p.Phe285Leu, p.Phe285Ser, p.Phe285Cys) have been reported as pathogenic (Tartaglia et al. 2002. PubMed ID: 11992261; Tartaglia et al. 2006. PubMed ID: 16358218; Hung et al. 2007. PubMed ID: 17339163; Ferrero et al. 2008. PubMed ID: 18678287). This variant is interpreted as likely pathogenic.
Invitae	RCV003539766	SCV004282398	uncertain significance	RASopathy	2023-03-13	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. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 15689434, 15996221, 23771920). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 40527). 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 phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Val).