rs397507507
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_002834.5(PTPN11):c.178G>A(p.Gly60Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G60A) has been classified as Pathogenic.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.178G>A | p.Gly60Ser | missense_variant | 3/16 | ENST00000351677.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.178G>A | p.Gly60Ser | missense_variant | 3/16 | 1 | NM_002834.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460980Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726844
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 11, 2023 | The PTPN11 c.178G>A; p.Gly60Ser variant (rs397507507) is reported in multiple individuals with PTPN11-associated disorders and reported to occur de novo in most of these individuals (Bertelloni 2013, Ezquieta 2012). This variant is also reported in ClinVar (Variation ID: 40490). It is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.89). Based on available information, this variant is considered to be pathogenic. References: Bertelloni S et al. IGF-I generation test in prepubertal children with Noonan syndrome due to mutations in the PTPN11 gene. Hormones (Athens). 2013 Jan-Mar;12(1):86-92. PMID: 23624134. Ezquieta B et al. Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy. Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. English, Spanish. PMID: 22465605. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 14, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); The majority of missense variants in this gene are considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22465605, 36349709, 23624134, 11992261, 9491886, 16053901, 29493581) - |
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 60 of the PTPN11 protein (p.Gly60Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 22465605, 23624134). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40490). 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.Gly60 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 16643459, 17020470, 24039098, 26817465). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2024 | Variant summary: PTPN11 c.178G>A (p.Gly60Ser) results in a non-conservative amino acid change located in the SH2 domain (IPR000980) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250992 control chromosomes (gnomAD). c.178G>A has been reported in the literature as de novo in individuals affected with Noonan Syndrome (example: Ezquieta_2012). These data indicate that the variant is likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 22465605). ClinVar contains an entry for this variant (Variation ID: 40490). Based on the evidence outlined above, the variant was classified as pathogenic. - |
See cases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Sep 04, 2023 | ACMG categories: PS1,PM1,PM2 - |
PTPN11-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 03, 2023 | The PTPN11 c.178G>A variant is predicted to result in the amino acid substitution p.Gly60Ser. This variant has been reported in individuals with Noonan syndrome/RASopathy phenotypes, with at least one case confirmed to have occurred de novo (Ezquieta et al. 2012. PubMed ID: 22465605; Bertelloni et al. 2013. PubMed ID: 23624134). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different amino acid substitutions affecting the same amino acid (p.Gly60Cys, p.Gly60Ala, p.Gly60Val) have been reported in individuals with Noonan syndrome (Human Gene Mutation Database). The c.178G>A (p.Gly60Ser) variant is interpreted as pathogenic. - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 31, 2017 | The p.Gly60Ser variant in PTPN11 has been previously identified in three individ uals with clinical features of Noonan syndrome (Ezquieta 2012, LMM unpublished d ata), was noted to have occurred de novo in one individual, and was absent from large population studies. In addition, several other amino acid changes at this position (p.Gly60Ala, p.Gly60Cys, p.Gly60Val) have been observed in individuals with clinical features of Noonan syndrome, suggesting that changes to this resid ue are not tolerated. In summary, this variant meets our criteria to be classifi ed as pathogenic for Noonan syndrome in an autosomal dominant manner based on it s de novo occurrence, absence from large population databases and multiple varia nts affecting this codon in individuals with features of Noonan syndrome. - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at