ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1529A>G (p.Gln510Arg) (rs121918470)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414743 SCV000490887 pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing The Q510R variant in the PTPN11 gene has been reported previously in association with Noonan syndrome and LEOPARD syndrome (Bertola et al., 2005; Carcavilla et al., 2013). The Q510R variant is observed in 1/33582 (0.003%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The Glutamine 510 codon appears to be a variant hot spot" in the PTPN11 gene located within a highly conserved portion of the Tyrosine-protein phosphatase domain. The Q510R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Other missense variants in the same residue (Q510E, Q510H, Q510P) and in nearby residues (Q506P, T507K) have been reported in the Human Gene Mutation Database in association with PTPN11-related disorders, some of whom also had HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret Q510R as a pathogenic variant"
Integrated Genetics/Laboratory Corporation of America RCV000780654 SCV000918107 likely pathogenic Rasopathy 2019-09-30 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1529A>G (p.Gln510Arg) results in a conservative amino acid change located in the PTP type protein phosphatase domain (IPR000242) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Other alterations of codon Q510 have been reported in patients with NS, LEOPARD syndrome, and ALL (Q510K, Q510E, Q510P-Aoki_PTPN11_HM_2008, PMID: 18470943) indicating Q510 is a mutational hotspot. The variant allele was found at a frequency of 4e-06 in 251892 control chromosomes. c.1529A>G has been reported in the literature in individuals affected with features of Neurofibromatosis/Noonan syndrome (Bertola_2005), LEOPARD syndrome (Carcavilla_2013), megalencephaly-capillary malformation syndrome (MCAP) (Docker_2015), suspected/diagnosed Noonan syndrome (Ezquieta_2012, Atik_2016), and one case report of Ewing sarcoma (Brohl_2017). The variant was reported as a de-novo occurrence in at-least two of these studies although the presenting phenotype was MCAP (with paternity confirmed) in one and NS (assumed paternity due to lack of traceable evidence) in the other (Docker_2015, Atik_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, until additional reports of its presence in individuals diagnosed with Noonan syndrome and/or experimental evidence demonstrating an impact on function are reported, the variant was classified as likely pathogenic.
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV001002770 SCV000992415 pathogenic LEOPARD syndrome 1 criteria provided, single submitter case-control
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414743 SCV001247475 pathogenic not provided 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000014273 SCV000034522 pathogenic Noonan syndrome 1 2005-07-30 no assertion criteria provided literature only

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