ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1529A>C (p.Gln510Pro) (rs121918470)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000210036 SCV000886028 pathogenic not provided 2018-01-22 criteria provided, single submitter clinical testing PTPN11:c.1529A>C; p.Gln510Pro is a well-known variant shown to co-segregate with disease in multiple families with LEOPARD syndrome (LS) (Kalidas 2005, Keren 2004), and has been identified in mixed cohorts of LS and Noonan syndrome (NS) patients (Tartaglia 2006 and Brasil 2010). This variant was shown to occur de novo in a four year old child with features of NS, although the age of the patient may have precluded a more accurate diagnosis of LS (Brasil 2010). Like other PTPN11 variants associated with LS, p.Gln510Pro has been shown to have a negative effect on PTP activity in cell culture, whereas variants associated with NS have a positive effect (Hanna 2006 and Edouard 2010). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database) but has been report to ClinVar as pathogenic by an expert panel (Variation ID: 13344). Based on these observations the p.Gln510Pro variant has been classified as pathogenic.
ClinGen RASopathy Variant Curation Expert Panel RCV000520822 SCV000616410 pathogenic Noonan syndrome with multiple lentigines 2017-04-03 reviewed by expert panel curation The c.1529A>C (p.Gln510Pro) variant in PTPN11 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). The p.Gln510Pro variant in PTPN11 has been reported in the literature to segregate with clinical features of a RASopathy in at least 4 family members (PP1_Moderate; APHP-Robert Debré Hospital: GTR Lab ID: 28338). The variant has also been identified in at least 2 independent occurrences in patients with clinical features of a RASopathy (PS4_Supporting; Partners LMM, GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data, APHP-Robert Debré Hospital; SCV000057459.14; SCV000200027.4; SCV000265844.1;. PMID 15520399, 20578946). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in PTPN11, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510Pro variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PS2_VeryStrong, PP1_Moderate, PM2, PP2, PP3, PS4_Supporting.
GeneDx RCV000210036 SCV000057459 pathogenic not provided 2018-01-04 criteria provided, single submitter clinical testing The Q510P missense variant has been reported previously in association with Noonan syndrome spectrum disorders (Keren et al., 2004; Kalidas et al., 2005; Brasil et al., 2010). Functional studies show Q510P leads to negligible catalytic activity and has a dominant positive effect on AKT activation (Hanna et al., 2006; Edouard et al., 2010). This variant is not observed in large population cohorts (Lek et al., 2016). The Q510P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014). Other missense variants at the same residue (Q510H, Q510R, Q510E) has also been seen in individuals with Noonan syndrome spectrum disorders (Bertola et al., 2005; Ganigara et al., 2011; Wakabayashi et al., 2011). Based on currently available evidence, we consider Q510P to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586289 SCV000698059 pathogenic Noonan syndrome 3 2017-04-10 criteria provided, single submitter clinical testing Variant summary: The PTPN11 c.1529A>C (p.Gln510Pro) variant involves the alteration of a highly conserved nucleotide in the Protein-tyrosine phosphatase, catalytic domain of the protein (InterPro). 5/5 in silico tools predict a damaging outcome for this variant and results of the functional study proved defective enzyme activity (Edouard, 2010). The variant of interest is absent from 121582 control chromosomes. The c.1529A>C has been reported in multiple affected individuals/families, with evidence of co-segregation of variant with disease (Keren, 2004; Kalidas, 2005; Brasil, 2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000033554 SCV000549999 pathogenic Rasopathy 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 510 of the PTPN11 protein (p.Gln510Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (rs121918470, ExAC no frequency). This variant has been reported to segregate with Noonan syndrome with multiple lentigines (NSML; formerly known as LEOPARD syndrome) in two families (PMID: 15690106, 15520399) and has also been reported in individuals with NSML and Noonan syndrome (PMID: 15520399, 16358218, 20578946). In at least one of these individuals, the variant occurred de novo (PMID: 20578946). ClinVar contains an entry for this variant (Variation ID: 13344). Experimental studies have shown that this missense change abolishes PTPN11 phosphatase activity in vitro and in cell culture (PMID: 16638574, 20308328). A different missense substitution at this codon (p.Gln510Glu) has been determined to be pathogenic (PMID: 21677813, 25708222, 22058153). This suggests that the glutamine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824752 SCV000200027 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2014-07-28 criteria provided, single submitter clinical testing The p.Gln510Pro variant in PTPN11 has been reported in at least 10 individuals w ith clinical features of LEOPARD syndrome and Noonan syndrome (Tartaglia 2006, K alidas 2005, Keren 2004, LMM upublished data) and segregated with disease in 3 a ffected relatives from 2 families (Kalidas 2005, Keren 2004). It has not been id entified in large population studies. Studies have shown that the Gln510Pro vari ant impacts protein function by decreasing the phosphatase activity of the prote in (Hanna 2006). In addition, a second variant at this codon (Gln510Glu) has be en identified more than 10 affected individuals and occurred de novo in at least one individual, suggesting that changes to this residue are not tolerated. In summary, this variant meets our criteria to be classified as pathogenic for Noon an spectrum disorders in an autosomal dominant manner.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000210036 SCV000265844 pathogenic not provided 2015-09-30 criteria provided, single submitter clinical testing
OMIM RCV000014272 SCV000034521 pathogenic LEOPARD syndrome 1 2010-05-01 no assertion criteria provided literature only

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