ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1232C>T (p.Thr411Met)

dbSNP: rs121918467
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV001030087 SCV001192880 uncertain significance RASopathy 2019-12-05 reviewed by expert panel curation The c.1232C>T (p.Thr411Met) variant PTPN11 is present in 0.003% (3/113264) non-Finnish European alleles in gnomAD. The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Observed cases from laboratories and publications lack sufficient clinical phenotypic information to support or refute pathogenicity (Institut Universitaire d'Hematologie internal data; Institute of Human Genetics, University Hospital Magdeburg, Germany internal data; PMID:15384080). In summary, the clinical significance of the p.Thr411Met variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000014269 SCV000999281 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001091427 SCV001247467 uncertain significance not provided 2019-07-01 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV001293768 SCV001480521 likely pathogenic Acute megakaryoblastic leukemia in down syndrome 2020-09-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001091427 SCV001714428 uncertain significance not provided 2019-09-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001030087 SCV002267893 uncertain significance RASopathy 2024-10-30 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 411 of the PTPN11 protein (p.Thr411Met). This variant is present in population databases (rs121918467, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 15384080). ClinVar contains an entry for this variant (Variation ID: 13341). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PTPN11 protein function with a negative predictive value of 80%. 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.
Ambry Genetics RCV002362582 SCV002666108 uncertain significance Cardiovascular phenotype 2023-06-08 criteria provided, single submitter clinical testing The p.T411M variant (also known as c.1232C>T), located in coding exon 11 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1232. The threonine at codon 411 is replaced by methionine, an amino acid with similar properties. In one study, this alteration was detected in three individuals from one family: one who met diagnostic criteria for Noonan syndrome and two who showed some symptoms, but did not meet formal diagnostic criteria. In addition, this alteration was not detected in two unaffected individuals from the same family (Bertola DR et al. Am. J. Med. Genet. A, 2004 Nov;130A:378-83). This alteration has also been noted in a stillbirth cohort (Stanley KE et al. N Engl J Med, 2020 Sep;383:1107-1116). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
OMIM RCV000014269 SCV000034518 pathogenic Noonan syndrome 1 2004-11-01 no assertion criteria provided literature only

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