Total submissions: 22
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000156985 | SCV000053297 | pathogenic | Noonan syndrome | 2019-04-06 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.218C>T (p.Thr73Ile) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 276806 control chromosomes. c.218C>T has been reported in the literature in multiple individuals affected with Noonan Syndrome and Juvenile Myelomonocyttic Leukema (JMML) (Tartaglia_2002, Tartaglia_2003, Niihori_2005, Kratz_2005, Kosaki_2002, Jongmans_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in enhanced phosphatase activity of mutant SHP-2. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
Gene |
RCV000212891 | SCV000057380 | pathogenic | not provided | 2024-02-20 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate the variant results in increased activity compared to wild type (PMID: 15987685); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35050212, 34850017, 32164556, 23832011, 23446178, 24803665, 24718990, 26286251, 15928039, 20383758, 30355600, 28106910, 26918529, 30050098, 30378271, 29907801, 31219622, 31560489, 32144894, 32901917, 28191889, 35792504, 34974531, 11992261, 9491886, 29493581, 16053901, 15987685) |
Laboratory for Molecular Medicine, |
RCV000156985 | SCV000200000 | pathogenic | Noonan syndrome | 2016-10-12 | criteria provided, single submitter | clinical testing | proposed classification - variant undergoing re-assessment, contact laboratory |
Center for Pediatric Genomic Medicine, |
RCV000212891 | SCV000511497 | pathogenic | not provided | 2016-10-28 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000515312 | SCV000611305 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2017-05-18 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000033475 | SCV000821663 | pathogenic | RASopathy | 2023-07-25 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome, Noonan-syndrome associated myeloproliferative disorder (PMID: 11992261, 14644997, 15240615, 15928039, 17020470, 17339163, 20383758, 23446178, 23832011). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 13334). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt PTPN11 function. Experimental studies have shown that this missense change affects PTPN11 function (PMID: 15987685, 24718990). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 73 of the PTPN11 protein (p.Thr73Ile). |
Baylor Genetics | RCV000014262 | SCV001522576 | pathogenic | Noonan syndrome 1 | 2022-11-01 | criteria provided, single submitter | clinical testing | |
3billion | RCV000014262 | SCV002012113 | pathogenic | Noonan syndrome 1 | 2021-10-02 | criteria provided, single submitter | clinical testing | Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000013334.14, PMID: 25097206, 23446178, and 20383758, PS2, PS4). The missense variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PM1). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Thr73Leu) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000044604.2, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.956, 3Cnet: 0.996, PP3). Patient's phenotype is considered compatible with Noonan syndrome (3billion dataset, PP4).Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
Revvity Omics, |
RCV000212891 | SCV002019557 | pathogenic | not provided | 2019-09-21 | criteria provided, single submitter | clinical testing | |
Genome Diagnostics Laboratory, |
RCV001813199 | SCV002060928 | pathogenic | Noonan syndrome and Noonan-related syndrome | 2021-05-25 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002415414 | SCV002725347 | pathogenic | Cardiovascular phenotype | 2016-04-01 | criteria provided, single submitter | clinical testing | The p.T73I pathogenic mutation (also known as c.218C>T), located in coding exon 3 of the PTPN11 gene, results from a C to T substitution at nucleotide position 218. The threonine at codon 73 is replaced by isoleucine, an amino acid with similar properties. This mutation has been described in the literature in multiple individuals with Noonan syndrome (Tartaglia M, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Kosaki K, J. Clin. Endocrinol. Metab. 2002 Aug; 87(8):3529-33) as well as in Noonan patients with accompanying Myeloproliferative disorders (MPD) or Juvenile myelomonocytic leukemia (JMML) (Kratz CP, Blood 2005 Sep; 106(6):2183-5. T; Niihori T, J. Hum. Genet. 2005; 50(4):192-202). This alteration has also been reported as a somatic mutation in individuals with hematologic malignancies (Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). In addition, functional studies have shown a statistically significant increase in phosphatase activity in cells expressing the p.T73I mutation, when compared to wild-type (Niihori T, J. Hum. Genet. 2005; 50(4):192-202; Tartaglia M, Am. J. Hum. Genet. 2006 Feb; 78(2):279-90). Based on the supporting evidence, p.T73I is interpreted as a disease-causing mutation. |
Ce |
RCV000212891 | SCV002821737 | pathogenic | not provided | 2024-05-01 | criteria provided, single submitter | clinical testing | PTPN11: PM1, PM2, PS2:Moderate, PS3:Moderate, PS4:Moderate, PP2, PP3 |
Baylor Genetics | RCV003147287 | SCV003835334 | pathogenic | Metachondromatosis | 2022-11-01 | criteria provided, single submitter | clinical testing | |
Baylor Genetics | RCV003147288 | SCV003835870 | pathogenic | LEOPARD syndrome 1 | 2022-11-01 | criteria provided, single submitter | clinical testing | |
Institute of Medical Genetics and Genomics, |
RCV000014262 | SCV004098990 | pathogenic | Noonan syndrome 1 | 2023-10-27 | criteria provided, single submitter | clinical testing | This heterozygous mis-sense variant is identified in a 3 month male with congenital heart disease, facial dysmorphism, FTT, juvenial myelomonocytic leukemia and echogenic kidney. This nucleotide change is absent in gnomAD database [PM2]. Insilico prediction [REVEL=0.95] predicts deleterious nature of this variant [PP3: Strong]. A clinvar entry for this variant is available. This variant is submitted to clinvar database [Variation ID: 13334] with “conflicting interpretation of pathogenicity, ”Pathogenic (14); Uncertain Significance (1)” interpretation by multiple submitter [PP5]. Based on the clinical correlation and available evidence, this variant is classified as "Pathogenic". |
Juno Genomics, |
RCV000014262 | SCV005416664 | pathogenic | Noonan syndrome 1 | criteria provided, single submitter | clinical testing | PM2_Supporting+PP2+PP3_Strong+PS4 | |
OMIM | RCV000014262 | SCV000034510 | pathogenic | Noonan syndrome 1 | 2005-04-15 | no assertion criteria provided | literature only | |
Institute of Molecular Pathology and Immunology of the University of Porto |
RCV000014262 | SCV000143816 | not provided | Noonan syndrome 1 | no assertion provided | not provided | ||
Baylor Genetics | RCV000033475 | SCV000196660 | pathogenic | RASopathy | no assertion criteria provided | clinical testing | Variant classified using ACMG guidelines | |
ARUP Laboratories, |
RCV000156985 | SCV000206707 | pathogenic | Noonan syndrome | 2012-06-12 | no assertion criteria provided | clinical testing | |
Diagnostic Laboratory, |
RCV000212891 | SCV001743328 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, |
RCV000212891 | SCV001953497 | pathogenic | not provided | no assertion criteria provided | clinical testing |