ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1381G>A (p.Ala461Thr) (rs121918468)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033530 SCV000057435 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing The A461T missense mutation in the PTPN11 gene has been reported previously in association with autosomal dominant LEOPARD syndrome (LS) (Yoshida et al., 2009; Chu et al., 2013). Another missense mutation altering the same codon, A461S, was also reported in LEOPARD syndrome (Osawa, 2009). The Alanine 461 codon lies in a PTP enzyme active site, which is a mutational hotspot in PTPN11. The variant is found in NOONAN panel(s).
GeneReviews RCV000055882 SCV000086888 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000587622 SCV000698054 pathogenic Noonan syndrome 3 2016-06-12 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.1381G>A (p.Ala461Thr) variant is a missense variant that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome for this variant. The variant is located within conserved PTP loop and was shown to strongly inhibiting EGF-evoked Erk activation in a dominant-negative manner. The variant is absent from the control population datasets of ExAC but was identified in several individuals with clinical features of NSRD, including de novo occurrences. The variant has been reported as Pathogenic by multiple clinical laboratories/reputable databases. Taken together, the variant is classified as Pathogenic.
Invitae RCV000529342 SCV000659032 pathogenic Rasopathy 2017-07-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 461 of the PTPN11 protein (p.Ala461Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with LEOPARD syndrome (PMID: 23799168, 15470362, 15389709). In two of these individuals, it was shown to arise de novo. ClinVar contains an entry for this variant (Variation ID: 13342). Experimental studies have shown that this missense change is catalytically inactive and exerts a dominant-negative effect (PMID: 16377799, 20493809, 24935154, 24718990). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037611 SCV000061272 pathogenic Noonan syndrome with multiple lentigines 2015-02-26 criteria provided, single submitter clinical testing The p.Ala461Thr variant in PTPN11 has been previously identified in 10 individua ls with clinical features of a LEOPARD (Sarkozy 2004, Yoshida 2004, Digilio 2010 , Chu 2013, LMM unpublished data) and occurred de novo in 3 of these individuals (Sarkozy 2004, Chu 2013, LMM unpublished data). It was absent from large popula tion studies. Furthermore, in-vitro and in-vivo functional studies suggest this variant has a dominant negative effect, which is an established pathogenic mecha nism in LEOPARD (Kontaridis 2006, Stewart 2010, Yu 2014). In summary, this varia nt meets our criteria to be classified as pathogenic for a LEOPARD (http://www.p
OMIM RCV000055882 SCV000034519 pathogenic LEOPARD syndrome 1 2004-11-01 no assertion criteria provided literature only

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