Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000159051 | SCV000208993 | likely pathogenic | not provided | 2023-06-15 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 31573083, 33009502, 29493581, 30896080) |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001526955 | SCV001737726 | likely pathogenic | RASopathy | 2021-06-07 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.854T>A (p.Phe285Tyr) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251350 control chromosomes (gnomAD). c.854T>A has been reported in the literature in individuals affected with Noonan syndrome or Noonan syndrome with multiple lentigines (Yu_2019). These data indicate that the variant may be associated with disease. Additionally, other variants at the same amino acid residue (Phe285Cys, Phe285Ile, Phe285Leu, Phe285Ser) have also been reported in association with Noonan syndrome, further supporting that this residue has clinical significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Ambry Genetics | RCV002408715 | SCV002676204 | pathogenic | Cardiovascular phenotype | 2018-08-03 | criteria provided, single submitter | clinical testing | The p.F285Y pathogenic mutation (also known as c.854T>A) is located in coding exon 8 of the PTPN11 gene. This change occurs in the first base pair of coding exon 8. The phenylalanine at codon 285 is replaced by tyrosine, an amino acid with highly similar properties. This mutation is located in the protein tyrosine phosphatase (PTP) functional domain of the SHP-2 protein, and is predicted to disrupt the interdomain interaction with the N-SH2 domain, which normally stabilizes the inactive conformation of the protein. Alterations at the same amino acid position (p.F285I, p.F285L, p.F285S and p.F285C) have been described in individuals with Noonan Syndrome (Tartaglia M et al, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Kosaki K et al, J. Clin. Endocrinol. Metab. 2002 Aug; 87(8):3529-33; Bertola DR et al, Genet. Test. 2006; 10(3):186-91; Tartaglia M et al, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90; Ferrero GB et al, Eur J Med Genet 2008 Jul; 51(6):566-72; Essawi ML et al, J. Formos. Med. Assoc. 2013 Nov; 112(11):707-12). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Service de Génétique Moléculaire, |
RCV001261017 | SCV001438414 | uncertain significance | Noonan syndrome | no assertion criteria provided | clinical testing |