12-112450508-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP2PP3PP5_Very_Strong
The NM_002834.5(PTPN11):c.328G>A(p.Glu110Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,534 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. E110G) 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 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTPN11 | NM_002834.5 | c.328G>A | p.Glu110Lys | missense_variant | 3/16 | ENST00000351677.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTPN11 | ENST00000351677.7 | c.328G>A | p.Glu110Lys | missense_variant | 3/16 | 1 | NM_002834.5 | A1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461534Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727094
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 21, 2014 | The p.Glu110Lys variant in PTPN11 has been previously identified in three indivi duals with clinical features of Noonan syndrome (Ezquieta 2012, Rodriguez 2014, LMM unpublished data) and was reported to have occurred de novo in two of these individuals (Ezquieta 2012, LMM unpublished data). It was absent from large popu lation studies (http://evs.gs.washington.edu/EVS/; dbSNP rs397507518). In summar y, the p.Glu110Lys variant in PTPN11 meets our criteria to be classified as path ogenic (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medici ne/). - |
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2023 | 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); This variant is associated with the following publications: (PMID: 22465605, 29907801, 24451042, 30050098, 35769956, 24150203, 29493581, 35979676) - |
Noonan syndrome 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 14, 2016 | - - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 18, 2018 | This sequence change replaces glutamic acid with lysine at codon 110 of the PTPN11 protein (p.Glu110Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with Noonan syndrome in the literature, including at least one individual where the variant was reported de novo (PMID: 22465605, 24150203, 24451042). ClinVar contains an entry for this variant (Variation ID: 40507). This variant is not present in population databases (ExAC no frequency). - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Aug 07, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at