ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.1381G>A (p.Ala461Thr) (rs121918468)

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Total submissions: 8
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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).
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in 10 individua ls with clinical features of a LEOPARD (Sarkozy 2004, Yoshida 2004, Digilio 2010 , Chu 2013, LMM unpublished data) and occurred de novo in 3 of these individuals (Sarkozy 2004, Chu 2013, LMM unpublished data).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
Invitae RCV000529342 SCV000659032 pathogenic Rasopathy 2019-09-29 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000529342 SCV000698054 pathogenic Rasopathy 2020-10-26 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1381G>A (p.Ala461Thr) results in a non-conservative amino acid change located in the PTP type protein phosphatase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251372 control chromosomes (gnomAD and publication data). c.1381G>A has been reported in the literature in multiple individuals with clinical features of NSRD, including de novo occurrences (Ypshida_2004, Chu_2011, Lee_2011, Digilio_2012, Ezquieta_2012, Croonen_2013, Leach_2019). These data indicate that the variant is very likely to be associated with disease. Functional studies report the variant effect results in catalytic inactivity and was shown to strongly inhibiting EGF-evoked Erk activation in a dominant-negative manner (Kontaridis_2006, Yu_2014). Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002017 SCV001159835 pathogenic not specified 2018-08-07 criteria provided, single submitter clinical testing The PTPN11 c.1381G>A; p.Ala461Thr variant (rs121918468) is reported in the literature in multiple individuals affected with LEOPARD syndrome and symptoms of Noonan syndrome (Chu 2013, Sarkozy 2004, Yoshida 2004). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13342) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant occurs in the protein tyrosine signature motif involved in phosphate binding (Kontaridis 2006, Sarkozy 2004, Yu 2014), and other variants associated with LEOPARD syndrome, including another variant at the same codon, p.Ala461Ser, have also been described in this domain (Yoshida 2004, Osawa 2009). Biochemical characterization of p.Ala461Thr PTPN11 variant protein shows severely reduced phosphatase activity (Kontaridis 2006, Yu 2014). This variant also fails to rescue developmental defects of a zebrafish shp2 (PTPN11) morphant to the same extent as wildtype (Bonetti 2014, Stewart 2010). The alanine at codon 461 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, the p.Ala461Thr variant is considered pathogenic. REFERENCES Bonetti M et al. Noonan and LEOPARD syndrome Shp2 variants induce heart displacement defects in zebrafish. Development. 2014 May;141(9):1961-70. Chu HS et al. Syndromic Hearing Loss in Association with PTPN11-Related Disorder: The Experience of Cochlear Implantation in a Child with LEOPARD Syndrome. Clin Exp Otorhinolaryngol. 2013 Jun;6(2):99-102. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. Osawa R et al. A novel PTPN11 missense mutation in a patient with LEOPARD syndrome. Br J Dermatol. 2009 Nov;161(5):1202-4. Sarkozy A et al. A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004 Dec;12(12):1069-72. Stewart RA et al. Phosphatase-dependent and -independent functions of Shp2 in neural crest cells underlie LEOPARD syndrome pathogenesis. Dev Cell. 2010 May 18;18(5):750-62. Yoshida R et al. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. Am J Med Genet A. 2004 Nov 1;130A(4):432-4. Yu ZH et al. Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations. Biochemistry. 2014 Jul 1;53(25):4136-51.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001089941 SCV001244985 pathogenic Noonan syndrome 1 2018-07-22 criteria provided, single submitter clinical testing A heterozygous missense variant, NM_002834.3(PTPN11):c.1381G>A, has been identified in exon 12 of the PTPN11 gene. The variant is predicted to result in a minor amino acid change from alanine to threonine at position 461 of the protein (NP_002825.3(PTPN11):p.(Ala461Thr)). The alanine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the active site of the PTPc (Tyrosine-protein phosphatase) domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic in multiple families with Noonan syndrome, and Noonan syndrome with multiple letigines, and has been shown to be de novo in several of these families (ClinVar, OMIM176876.0020). In addition, functional analysis has shown the variant exerts a dominant negative effect on the protein resulting in a catalytically inactive phosphatase (ClinVar). A different variant in the same codon resulting in a change to serine has also been shown to cause Noonan syndrome with multiple letigines (ClinVar). Analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
OMIM RCV000055882 SCV000034519 pathogenic LEOPARD syndrome 1 2004-11-01 no assertion criteria provided literature only
GeneReviews RCV000055882 SCV000086888 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.

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