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

gnomAD frequency: 0.00001  dbSNP: rs397507546

Total submissions: 11

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)
Labcorp Genetics (formerly Invitae), Labcorp	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001330778	SCV005086425	pathogenic	Noonan syndrome 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Both loss of function and gain of function are known mechanisms of disease for this gene. Metachondromatosis (MIM#156250) and Noonan syndrome with multiple lentigines have been associated with loss of function variants, whereas Noonan syndrome 1 (MIM#163950) is caused by gain of function variants (PMIDs: 11992261, 24935154, 21533187; ClinGen expert panel). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome is known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. p.(Gly503Ala) has been classified as pathogenic once, and p.(Gly503Arg) has been classified as pathogenic multiple times by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with Noonan syndrome (PMIDs: 18678287, 26785492). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign