ClinVar Genomic variation as it relates to human health

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germline of sev eral individuals with clinical features of Noonan syndrome (Kratz 2005, Tartagli a 2003, Lee 2008, LMM unpublished data).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.

Frequently observed as a somatic variant in patients with juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and/or myelodysplastic syndrome (MDS) (Tartaglia et al., 2003; Kratz et al., 2005; Tartaglia et al., 2006; Christiansen et al., 2007; Hou et al., 2008; Park et al., 2012; Stasik et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17972951, 12634870, 16518851, 21901340, 12717436, 14982869, 16358218, 17330262, 17353900, 28098151, 11992261, 9491886, 16053901, 29493581, 32786180, 34411415, 34958143, 34459887, 30868567, 15928039)

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.