rs397507540
Variant summary
Our verdict is Pathogenic. Variant got 23 ACMG points: 23P and 0B. PS1PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.1472C>A(p.Pro491His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P491A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 23 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.1472C>A | p.Pro491His | missense_variant | 13/16 | ENST00000351677.7 | |
PTPN11 | NM_001330437.2 | c.1484C>A | p.Pro495His | missense_variant | 13/16 | ||
PTPN11 | NM_001374625.1 | c.1469C>A | p.Pro490His | missense_variant | 13/16 | ||
PTPN11 | XM_011538613.3 | c.1481C>A | p.Pro494His | missense_variant | 13/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.1472C>A | p.Pro491His | missense_variant | 13/16 | 1 | NM_002834.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2019 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17020470, 24803665, 17546245, 30417923, 31560489) - |
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | May 04, 2017 | - - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 29, 2015 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Juvenile myelomonocytic leukemia;C0410530:Metachondromatosis;C4551484:LEOPARD syndrome 1;C4551602:Noonan syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 09, 2021 | - - |
Strabismus;C0349588:Short stature;C0424503:Abnormal facial shape Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Sep 02, 2021 | The c.1472C>A;p.(Pro491His) variant has been published as a pathogenic variant in association with Noonan syndrome (PMID: 17546245, 21590266, 17020470; GeneOne, DASA) - PS4; ClinVar contains an entry for this variant (Variation ID: 40551); This variant is not present in population databases (rs397507540 - gnomAD no frequency; ABraOM no frequency - abraom.ib.usp.br) - PM2; Missense variant in PTPN11 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (PMID: 29493581) - PP2; In silico analysis predicts this variant is probably damaging to the protein structure/function - PP3; Pathogenic missense variants in this residue (PMID: 20186801, 18470943, 23624134). In summary, the currently available evidence indicates that the variant is pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2018 | The p.P491H pathogenic mutation (also known as c.1472C>A), located in coding exon 13 of the PTPN11 gene, results from a C to A substitution at nucleotide position 1472. The proline at codon 491 is replaced by histidine, an amino acid with similar properties. This mutation was first described in an individual meeting clinical diagnostic criteria for Noonan syndrome (Bertola DR et al. Genet. Test., 2006;10:186-91). In addition, three disease-causing mutations: p.P491L, p.P491S, and p.P491T, have been described in the same codon (Binder G et al. J. Clin. Endocrinol. Metab., 2005 Sep;90:5377-81; Pierpont EI et al. Genes Brain Behav., 2009 Apr;8:275-82; Ezquieta B et al. Rev Esp Cardiol (Engl Ed), 2012 May;65:447-55). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 31, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro491 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15985475, 18470943, 20186801, 22781091, 23624134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40551). This missense change has been observed in individuals with Noonan syndrome (PMID: 17020470, 17546245, 21590266). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 491 of the PTPN11 protein (p.Pro491His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at