ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.182A>C (p.Asp61Ala) (rs121918461)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000156008 SCV000205720 likely pathogenic Noonan syndrome 2013-08-09 criteria provided, single submitter clinical testing The Asp61Ala variant has not been previously identified by our laboratory, nor h as it been identified in large population studies. This variant has been reporte d in the literature in one fetus with a diagnosis of Noonan syndrome and fetal c hylothorax (Chen 2009). In addition, two other variants at this position have be en identified in >25 individuals with clinical features of Noonan syndrome by ou r laboratory and in the literature (Asp61Asn and Asp61Gly; Loh 2004, Tartaglia 2 005, Tartaglia 2006, Kratz 2005, Yamamoto 2006, Kosaki 2002, Bertola 2006, Noord am 2008, Shaw 2007, Tartaglia 2001). The Asp residue at this position is highly conserved across evolutionarily distinct species, and computational analyses (bi ochemical amino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Asp61Ala variant may have impact to the protein. In summary, this variant is l ikely pathogenic, though additional studies are required to fully establish its clinical significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780656 SCV000918112 pathogenic Rasopathy 2018-08-20 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.182A>C (p.Asp61Ala) 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. The variant was absent in 245776 control chromosomes (gnomAD). The variant, c.182A>C, has been reported in the literature in a fetus affected with Noonan Syndrome and Related Conditions (Chen 2009). In addition, other variants affecting this position, Asp61Asn and Asp61Gly, has been reported in several affected individuals. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating an increased basal activity of protein tyrosine phosphatase (OReilly 2000). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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