12-112453279-G-T
Variant summary
Our verdict is Pathogenic. Variant got 21 ACMG points: 21P and 0B. PS1PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_002834.5(PTPN11):c.417G>T(p.Glu139Asp) variant causes a missense change. 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 Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in Lovd.
Frequency
Consequence
NM_002834.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 21 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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PTPN11 | ENST00000351677.7 | c.417G>T | p.Glu139Asp | missense_variant | Exon 4 of 16 | 1 | NM_002834.5 | ENSP00000340944.3 | ||
PTPN11 | ENST00000635625.1 | c.417G>T | p.Glu139Asp | missense_variant | Exon 4 of 15 | 5 | ENSP00000489597.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Identified in patients with features of PTPN11-related RASopathy in the literature and tested at GeneDx (PMID: 11992261); Published functional studies demonstrate a damaging effect (PMID: 20308328, 18372317); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22135187, 18372317, 23584145, 20308328, 24628801, 30355600, 21407260, 11992261, 22315187, 33318624) -
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Noonan syndrome 1 Pathogenic:2
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Inborn genetic diseases Pathogenic:1
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Noonan syndrome;C0349639:Juvenile myelomonocytic leukemia Pathogenic:1
The p.Glu139Asp (c.417G>T) variant in PTPN11 has been identified in 3 individua ls with Noonan syndrome (Tartaglia 2002, LMM unpublished data). It has not been identified in large population studies. In addition, another nucleotide change (c.417G>C) that results in the same amino acid change has also been reported in at least 10 individuals with Noonan syndrome, 1 individual with Noonan syndrome and acute lymphoblastic leukemia (ALL), 1 individual with Juvenile myelomonocyti c leukemia (JMML), and 1 individual with Noonan syndrome that developed ALL and JMML (Musante 2002, Loh 2004, Bertola 2006, Chan 2006, Hung 2007, Karow 2007, Ko 2008, Derbent 2010, Jongmans 2011, Pauli 2012, Timeus 2013). This variant has b een reported to show both familial segregation and to have occurred de novo (Jon gmans 2005, Houweling 2010). In summary, this variant meets our criteria to be c lassified as pathogenic (http://www.partners.org/personalizedmedicine/LMM). -
RASopathy Pathogenic:1
Experimental studies have shown that this missense change affects PTPN11 protein function (PMID: 18372317, 23584145, 20308328). This sequence change replaces glutamic acid with aspartic acid at codon 139 of the PTPN11 protein (p.Glu139Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 16358218, 19020799, 17339163). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 40512). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at