ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1124A>G (p.Tyr375Cys)

gnomAD frequency: 0.00001  dbSNP: rs41299183
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037606 SCV000061267 uncertain significance not specified 2010-11-05 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Tyr375Cys varia nt in PTPN11 has not previously been reported in the literature or been observed identified in our laboratory, although it is listed in dbSNP (rs41299183, not v alidated). Tyrosine (Tyr) at amino acid position 375 is not highly conserved in different species, and two different computational analyses predict this variant to have a benign effect on the function of the protein. However, in the absence of additional data, the clinical significance of this variant cannot be determi ned at this time.
Labcorp Genetics (formerly Invitae), Labcorp RCV001042982 SCV001206692 uncertain significance RASopathy 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the PTPN11 protein (p.Tyr375Cys). This variant is present in population databases (rs41299183, gnomAD 0.006%). 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: 40544). 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 not expected to disrupt PTPN11 protein function with a negative 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.
Fulgent Genetics, Fulgent Genetics RCV002477047 SCV002778713 uncertain significance Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2021-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV004017275 SCV004849255 uncertain significance Cardiovascular phenotype 2019-04-05 criteria provided, single submitter clinical testing The c.1124A>G (p.Y375C) alteration is located in exon 10 (coding exon 10) of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 1124, causing the tyrosine (Y) at amino acid position 375 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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