NM_002834.5:c.217_218delACinsCT
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP2PP3PP5_Very_Strong
The NM_002834.5(PTPN11):c.217_218delACinsCT(p.Thr73Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T73I) 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 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome 1 Pathogenic:1
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Noonan syndrome Pathogenic:1
The Thr73Leu variant in PTPN11 has previously been reported in the literature in one individual with clinical features of Noonan syndrome where it was reported to have occurred de novo (Ezquieta 2012). This variant was not identified in ei ther parent of this individual and therefore likely occurred de novo, assuming t hat non-medical explanations including alternate paternity or undisclosed adopti on have been ruled out In addition, a different amino acid change at this locati on (Thr73Ile) has previously been reported in the literature in many individuals with Noonan syndrome and Noonan syndrome with Juvenile myelomonocytic leukemia or myelodysplasia (Tartaglia 2003, Kratz 2005, Tartaglia 2006, Jongmans 2005) an d is classified as pathogenic in our laboratory. The evidence above taken togeth er supports that this variant is disease causing and responsible for Noonan synd rome and possibly Juvenile myelomonocytic leukemia or myelodysplasia in this ind ividual. In summary, this variant meets our criteria to be classified as pathoge nic (http://pcpgm.partners.org/LMM). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at