ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.683G>T (p.Ser228Ile)

dbSNP: rs748085966
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000658340 SCV000780112 uncertain significance not provided 2018-05-23 criteria provided, single submitter clinical testing The S228I variant of uncertain significance in the PTPN11 gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In addition, S228I 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Fulgent Genetics, Fulgent Genetics RCV005010640 SCV005632291 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2024-04-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV005091893 SCV005818864 uncertain significance RASopathy 2024-05-23 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 228 of the PTPN11 protein (p.Ser228Ile). This variant is present in population databases (rs748085966, gnomAD 0.0009%). 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: 546460). 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.

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