ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1402A>C (p.Thr468Pro) (rs397507537)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000033532 SCV000057437 pathogenic not provided 2015-12-09 criteria provided, single submitter clinical testing The T468P missense mutation in the PTPN11 gene has been reported previously in association with LEOPARD syndrome (Seishima, et al., 2007). Another missense mutation affecting the same codon (T468M) has been reported in patients with LEOPARD syndrome (Degilio et al., 2002). These mutations lie in the PTP domain of the encoded protein which plays an essential role in catalytic activity. Threonine 468 is conserved in several related tyrosine phosphatases, suggesting that it is integral to PTP-domain function. The variant is found in NOONAN panel(s).
Invitae RCV000231162 SCV000287693 pathogenic Rasopathy 2017-06-29 criteria provided, single submitter clinical testing This sequence change replaces threonine with proline at codon 468 of the PTPN11 protein (p.Thr468Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline. This variant is not present in population databases (rs397507537, ExAC no frequency). This variant has been reported in individuals affected with Noonan Syndrome with Multiple Lentigines (NSML) (also known as LEOPARD syndrome) (PMID: 17927788, 25917897). ClinVar contains an entry for this variant (Variation ID: 40547). Structural analyses have reported that the threonine residue at codon 468 is located in a functionally important region of the PTPN11 protein (PMID: 16377799, 18372317). Lesional skin from an individual with this variant had increased immunohistochemical staining for activated Akt, mTOR, and STAT3 compared to unaffected individuals, suggesting that this variant may affect the catalytic PTP domain (PMID: 25917897). A different missense substitution at this codon (p.Thr468Met) has been determined to be pathogenic (PMID: 12058348, 16377799, 18372317). This suggests that the threonine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this is a rare variant that has been reported in individuals affected with NSML and resides in an important catalytic domain of the PTPN11 protein. For these reasons, this variant has been classified as Pathogenic.

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