ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.214G>A (p.Ala72Thr) (rs121918453)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824740 SCV000204031 likely pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2015-02-11 criteria provided, single submitter clinical testing The p.Ala72Thr variant in PTPN11 has been identified by our laboratory as a de n ovo occurrence in one fetus with an increased NT measurement. It was absent from large population studies. This variant has also been reported as a somatic chan ge in at least 5 individuals with juvenile myelomonocytic leukemia (JMML; Kratz 2005, Tartaglia 2006). In addition, different amino acid changes at this positio n (p.Ala72Ser, p.Ala72Gly, p.Ala72Pro) have been reported in the germline of sev eral individuals with clinical features of Noonan syndrome (Kratz 2005, Tartagli a 2003, Lee 2008, LMM unpublished data). Computational prediction tools and cons ervation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, alt hough additional studies are required to fully establish its clinical significan ce, the p.Ala72Thr variant is likely pathogenic.
GeneDx RCV000680626 SCV000808069 pathogenic not provided 2018-03-12 criteria provided, single submitter clinical testing The A72T missense variant in the PTPN11 gene has been reported previously as an apparently de novo occurrence in association with nuchal translucency, cystic hygroma, and hydrops fetalis in a fetus (Mason-Suares et al., 2017). The variant is not observed in large population cohorts (Lek et al., 2016). A72T is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The variant is located within the SH2 domain, which is a hot spot for Noonan syndrome variants and is a site involved in switching the protein between its inactive and active conformations. Missense variants in the same residue (A72S/G/P) and in nearby residues (F71I/L, T73I, E76D/G/V) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000154367 SCV000918109 pathogenic Rasopathy 2019-07-29 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.214G>A (p.Ala72Thr) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Overlapping variants at Ala72 and adjacent codons have been implicated in Noonan syndrome (e.g., p.A72G, p.A72P, p.A72S), suggesting the codon and motif are critical for proper protein function. The variant was absent in 251056 control chromosomes. c.214G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions such as JMML, and prenatally diagnosed CHD/Noonan syndrome ((Kratz_2005, Mason-Suares_2017, Westphal_2019). One of these publications reported the identification of this variant as a confirmed de-novo variant following trio-based exome sequence analysis (Westphal_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics,Klinikum rechts der Isar RCV000995620 SCV001149899 pathogenic Noonan syndrome 1 2018-03-27 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000443279 SCV000507232 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425277 SCV000507233 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435950 SCV000507234 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417864 SCV000507235 likely pathogenic Neuroblastoma 2016-05-31 no assertion criteria provided literature only

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