ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1530G>C (p.Gln510His) (rs397507550)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000521890 SCV000616416 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.1530G>C (p.Gln510His) variant in PTPN11 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, EGL, APHP-Robert Debré Hospital internal data; GTR ID's: 26957, 500060, 28338 ClinVar SCV000057460.11; SCV000331072.3). At least 2 other pathogenic missense variants have been previously identified at this codon of PTPN11 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40566, 13345, 13344). This variant was absent from large population studies (PM2; ExAC, The variant is located in the PTPN11 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Gln510His 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: PM6_Strong, PM5_Strong, PM2, PP3, PP2.
GeneDx RCV000077854 SCV000057460 pathogenic not provided 2018-01-09 criteria provided, single submitter clinical testing The Q510H missense mutation in the PTPN11 gene has been reported previously in a patient with LEOPARD syndrome, who developed progressive hypertrophic cardiomyopathy (HCM) with congestive heart failure and nonsustained ventricular tachycardia treated with an implantable cardioverter defibrillator (Wakabayashi et al., 2011). The Glutamine 510 codon appears to be a mutation hot spot" in the PTPN11 gene and is located within a highly conserved portion of the gene, which encodes the phosphotyrosine phosphatase (PTP) domain. Other mutations at this same codon (Q510E, Q510R, Q510P) have also been reported in individuals with Noonan syndrome and LEOPARD syndrome, some of whom also had hypertrophic cardiomyopathy (Ganigara et al., 2011; Digilio et al., 2006). Specifically, two patients with the Q510E mutation had severe biventricular obstructive HCM (Digilio et al., 2006). The variant is found in NOONAN panel(s)."
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077854 SCV000331072 likely pathogenic not provided 2015-12-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000521890 SCV000918110 pathogenic Rasopathy 2018-06-25 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.1530G>C (p.Gln510His) results in a non-conservative amino acid change affecting a critical amino acid located in the PTP type protein phosphatase of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 30972 control chromosomes. c.1530G>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One was the "ClinGen RASopathy Expert Panel" which classified this variant as Pathogenic, while the other classified it as "Likely Pathogenic" without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

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