ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.149C>T (p.Thr50Ile) (rs267606921)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211835 SCV000061231 pathogenic Noonan syndrome 2013-03-06 criteria provided, single submitter clinical testing The Thr50Ile variant has been reported in 2 individuals with clinical features o f Noonan syndrome (Cirstea 2010). This variant was reported to have occurred de novo in these individuals. Studies have shown that the Thr50Ile variant may impa ct protein function (Cirstea 2010, Runtuwene 2011). However, this in vitro assay may not accurately represent biological function. Computational analyses (bioch emical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Thr50Ile variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM).
Invitae RCV000463185 SCV000553464 pathogenic Rasopathy 2016-06-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 50 of the NRAS protein (p.Thr50Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in 3 individuals affected with Noonan Syndrome (PMID: 19966803, 22855653). In two of the individuals, parental testing was done, and the variant was shown to be de novo (PMID: 19966803). ClinVar contains an entry for this variant (Variation ID: 13902). Experimental studies have shown that this missense change [p.Thr50Ile] interacts with the polar heads of membrane phospolipids and is an integral part of a functional region controlling the orientation and signalling output of the RAS membrane (PMID: 19966803). Furthermore, studies using zebrafish embryos, showed severe developmental defects during epiboly and gastrulation, which is consistent with defects observed in known Noonan related genes (PMID: 21263000). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014916 SCV000035172 pathogenic Noonan syndrome 6 2010-01-01 no assertion criteria provided literature only
GeneReviews RCV000208537 SCV000264347 pathogenic Noonan syndrome 1 2016-02-25 no assertion criteria provided literature only

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