ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1508G>A (p.Gly503Glu)

gnomAD frequency: 0.00001  dbSNP: rs397507546
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033548 SCV000057453 pathogenic not provided 2022-01-28 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 18678287, 26785492, 25862627, 24803665, 22391158, 22138486, 21784522, 16358218, 24613412, 28628100, 19737548, 25363768, 28694526, 28991257, 28191890, 31036916, 32233106, 28714951, 33482836, 28191889, 32368696, 34011629, 31785789, 29493581)
Invitae RCV000532971 SCV000659035 pathogenic RASopathy 2022-06-13 criteria provided, single submitter clinical testing 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly503 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12960218, 16358218, 18758896, 19077116, 19737548, 24754368). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 40561). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 18678287, 26785492). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 503 of the PTPN11 protein (p.Gly503Glu).
Eurofins Ntd Llc (ga) RCV000033548 SCV000709442 likely pathogenic not provided 2017-06-28 criteria provided, single submitter clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677651 SCV000803786 pathogenic LEOPARD syndrome 1 2017-08-17 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330778 SCV001522572 pathogenic Noonan syndrome 1 2023-09-14 criteria provided, single submitter clinical testing
3billion RCV001330778 SCV002521218 pathogenic Noonan syndrome 1 2022-05-22 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040561). A different missense change at the same codon (p.Gly503Arg) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040558, VCV000040559, VCV000571101). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001330778 SCV002759349 pathogenic Noonan syndrome 1 2022-12-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490448 SCV002803122 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2022-01-07 criteria provided, single submitter clinical testing
Baylor Genetics RCV000677651 SCV004183538 pathogenic LEOPARD syndrome 1 2023-09-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV003450655 SCV004183548 pathogenic Metachondromatosis 2023-09-09 criteria provided, single submitter clinical testing

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