ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.772G>A (p.Glu258Lys)

dbSNP: rs1279770165
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV001262011 SCV001439376 likely pathogenic Noonan syndrome 1 2020-09-03 criteria provided, single submitter research ACMG codes:PM1, PM2, PM5, PP2, PP3
MGZ Medical Genetics Center RCV001262011 SCV002580624 likely pathogenic Noonan syndrome 1 2022-02-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV004987013 SCV005478397 uncertain significance Cardiovascular phenotype 2024-07-15 criteria provided, single submitter clinical testing The c.772G>A (p.E258K) alteration is located in exon 7 (coding exon 7) of the PTPN11 gene. This alteration results from a G to A substitution at nucleotide position 772, causing the glutamic acid (E) at amino acid position 258 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV005094247 SCV005777635 uncertain significance RASopathy 2024-12-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 258 of the PTPN11 protein (p.Glu258Lys). This variant is not present in population databases (gnomAD no frequency). 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: 982429). 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 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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