Submissions for variant NM_002834.5(PTPN11):c.174C>A (p.Asn58Lys)

dbSNP: rs397507506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000157677	SCV000057361	pathogenic	not provided	2023-06-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34184824, 26633542, 29212898, 28911804, 30050098, 29907801, 11992261, 9491886, 16053901, 29493581, 34782754)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037629	SCV000061291	pathogenic	Noonan syndrome	2021-04-28	criteria provided, single submitter	clinical testing	The p.Asn58Lys (c.174C>A) variant in PTPN11 has been reported in at least six individuals with Noonan syndrome and segregated with disease in one affected family member (Chan 2006, Miller 2017 PMID: 29212898, Sublett 2017 PMID: 28911804, D'Amico 2021 PMID: 33811550, LMM data). It has also been reported in one individual with multiple congenital anomalies (Retterer 2015 PMID:26633542). It was absent from large population studies, but has been reported in ClinVar (Variation ID 40488). Another variant resulting in the same amino acid change (c.174C>G) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have been identified in individuals with Noonan syndrome and are classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP Criteria applied: PS1, PS4, PM5_Strong, PM2_Supporting.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556984	SCV000659040	pathogenic	RASopathy	2022-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). A different variant (c.174C>G) giving rise to the same protein effect has been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 40488). 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. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12634870, 15001945, 15956085, 16263833, 16358218, 19125092, 20954246, 21204800, 22190897, 23321623, 23624134, 23756559, 25914815). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587067	SCV000698062	pathogenic	Noonan syndrome 3	2016-01-25	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and polar Asparagine (N) with a large size and basic Lysine (K). 4/4 in silico tools predict the variant to be disease causing. It is absent from the large and broad cohorts of the ExAC project while it was found in several NS patients either as a de novo or as a familiar mutation suggesting pathogenicity. Variants affecting the same amino acid, Asn58His and Asn58Asp, Asn58Tyr have been reported by our laboratory in the pathogenic spectrum suggesting the Asn58 residue to be a mutational hotspot and further supporting a casual outcome for the variant. Furthermore, clinical diagnostic centers classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant was classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001358687	SCV001554497	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813243	SCV002060750	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-10-01	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004795945	SCV005418760	pathogenic	Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1		criteria provided, single submitter	clinical testing	PM2+PS1+PM5_Strong+PS4_Moderate+PP2
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157677	SCV000207648	pathogenic	not provided	2015-01-15	no assertion criteria provided	clinical testing