ClinVar

Description

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.