ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.227A>T (p.Glu76Val) (rs121918465)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788241 SCV000927291 pathogenic not provided 2017-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781775 SCV000920095 pathogenic Rasopathy 2017-12-10 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.227 A>T (p.Glu76Val) variant involves the alteration of a highly conserved nucleotide. The variant is located within the N-terminal SH2 domain and mutations in this domain are leading to constitutive activation of tyrosine phosphatase and, therefore, associated with oncogenesis (Panday_2017). 4/4 in silico tools used predict a damaging outcome for this variant and constitutive activation of SHP2 was confirmed by functional studies (Li_2014). This variant is absent from 245868 control chromosomes of gnomAD dataset, however was identified as a somatic event in multiple JMML and AML patients. The codon E76 is reportedly a hot-spot mutation, frequently identified in JMML (Tartaglia_2006, Park_2012). The variant was identified as a de novo germline event in a fetal sample with a severe presentation including a 11-mm nuchal translucency, cystic hygroma, fetal hydrops, hydrothorax, and generalized skin edema (Croonen_2013). Additionally, another abnormal prenatal case with alteration of the same codon has been recently reported (Mason-Suares_2017). Taken together, this variant is classified as Pathogenic.
OMIM RCV000014265 SCV000034514 pathogenic Juvenile myelomonocytic leukemia 2003-06-01 no assertion criteria provided literature only

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