ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1190C>T (p.Thr397Met)

gnomAD frequency: 0.00002  dbSNP: rs767503386
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000321441 SCV000329567 uncertain significance not provided 2016-11-22 criteria provided, single submitter clinical testing The T397M variant in the PTPN11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T397M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T397M as a variant of uncertain significance, which may be related to the reported speech delay, ventricular tachycardia, and cardiac hypertrophy in this individual.Although this individual's brother and father, neither of whom are reported to have clinical symptoms of a PTPN11-related disorder, also harbor the T397M variant, marked variable expressivity has been reported for PTPN11 pathogenic variants (Allanson et al., 2011).
Labcorp Genetics (formerly Invitae), Labcorp RCV000461011 SCV000549983 uncertain significance RASopathy 2023-11-15 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 397 of the PTPN11 protein (p.Thr397Met). This variant is present in population databases (rs767503386, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PTPN11-related conditions. ClinVar contains an entry for this variant (Variation ID: 279919). 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 with a positive predictive value of 95%. 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.
Genomic Medicine Lab, University of California San Francisco RCV001007903 SCV001167609 uncertain significance Noonan syndrome 1 2018-09-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV002338820 SCV002644546 uncertain significance Cardiovascular phenotype 2023-06-12 criteria provided, single submitter clinical testing The p.T397M variant (also known as c.1190C>T), located in coding exon 10 of the PTPN11 gene, results from a C to T substitution at nucleotide position 1190. The threonine at codon 397 is replaced by methionine, an amino acid with similar properties. This amino acid position is well 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.
Fulgent Genetics, Fulgent Genetics RCV005003599 SCV005632297 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2023-12-27 criteria provided, single submitter clinical testing

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