ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.182A>G (p.Asp61Gly) (rs121918461)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000077856 SCV000057369 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing The D61G missense variant in the PTPN11 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2001; van Trier et al., 2016; Piccini et al., 2017) and observed de novo in multiple cases tested at GeneDx. The variant was not observed in large population cohorts (Lek et al., 2016). D61G is a non-conservative amino acid substitution, within the range of directly interating residues between N-SH2 and PTPN domains (Uniprot). This is a hot spot for Noonan syndrome pathogenic variants, and is the first of two sites involved in switching between the inactive and active protein conformation. Additionally, studies in mice have shown that the D61G variant causes a phenotype similar to Noonan syndrome when in a heterozygous state, and is embryonic lethal when homozygous (Araki et al., 2004). Functional studies have also shown D61G leads to increased activity compared to wild type (Keilhack et al., 2005). Missense variants in the same residue (D61H, D61N, D61A) have been reported in association with Noonan syndrome, supporting the functional importance of this region of the protein (Chen et al., 2009; Houweling et al., 2010; Tartaglia et al., 2002). Based on currently available evidence, we consider D61G to be pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077856 SCV000058289 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824738 SCV000199995 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2015-07-14 criteria provided, single submitter clinical testing The p.Asp61Gly variant in PTPN11 has been previously reported in >30 individuals with Noonan syndrome with or without juvenile myelomonocytic leukemia (JMML) in cluding at least 5 de novo occurrences (Tartagila 2001, Kosaki 2002, Yoshida 200 4, Kratz 2005, Bertola 2006, Chan 2006, Shaw 2007, Noordam 2005, Strullu 2014, B ouchikhi 2015, LMM data). It was also identified as a somatic variant in 1 child with acute lymphoblastic leukemia (ALL) and 2 children with JMML (Yamamoto 2006 , Stullu 2014). It has not been identified in large population studies. Both in vivo animal models and in vitro studies provide evidence that this variant impac ts protein function (Araki 2004, Kontaridis 2006, Uhlen 2006, Eminaga 2008, Wang 2009, Xu 2010, De Rocca 2012, Bonetti 2014, Lee 2014). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndrome and JMML in an autosomal dominant manner.
Invitae RCV000033464 SCV000549993 pathogenic Rasopathy 2019-08-09 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 61 of the PTPN11 protein (p.Asp61Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (rs121918461, ExAC no frequency). This is one of the most commonly reported variants in individuals affected with Noonan syndrome (PMID: 11704759, 11992261, 12634870, 15928039, 17020470, 22420426, 26084119, 16358218), and has also been reported in an individual affected with juvenile myelomonocytic leukemia (PMID:15928039 ). In at least two individuals affected with Noonan syndrome, this variant was shown to have arisen de novo (PMID: 23321623, 26242988). ClinVar contains an entry for this variant (Variation ID: 13330). Experimental studies have shown that this missense change results in increased basal activity compared to wild-type protein (PMID: 15987685, 16377799, 19008228). Knock-in experiments in mice resulted in phenotypes consistent with Noonan syndrome (PMID: 15273746). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626829 SCV000747532 pathogenic Short stature; Abnormality of cardiovascular system morphology 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000033464 SCV001338338 pathogenic Rasopathy 2020-02-29 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.182A>G (p.Asp61Gly) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251804 control chromosomes. c.182A>G has been well reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (example, Tartaglia_2001, Musante_2003, Bertola_2006, Kosaki_2002, Ferreira_2008, Strullu_2014). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a gain of function leading to activation of the Ras-ErK signaling pathway (example, Hu_2015). Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626829 SCV001368980 pathogenic Short stature; Abnormality of cardiovascular system morphology 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. This variant was detected in heterozygous state.
OMIM RCV000014258 SCV000034506 pathogenic Noonan syndrome 1 2002-08-01 no assertion criteria provided literature only
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000156984 SCV000206706 pathogenic Noonan syndrome 2011-11-01 no assertion criteria provided clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000077856 SCV000207650 pathogenic not provided 2015-01-15 no assertion criteria provided clinical testing

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