ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.246T>A (p.Phe82Leu) (rs730881014)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000427451 SCV000534935 pathogenic not provided 2017-08-14 criteria provided, single submitter clinical testing The c.246 T>A pathogenic variant has not been previously reported; however, two different nucleotide substitutions (c.246 T>G and c.246 T>C) resulting in the same amino acid substitution of a phenylalanine to a Leucine (F82L) at this residue have been reported in association with a RASopathy (Cavé et al., 2016; Aoki et al., 2013). Functional studies have shown that F82L is a gain-of-function variant that results in increased ELK1 transcriptional activation (Aoki et al., 2013). This c.246 T>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F82L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Other pathogenic amino acid substitutions at this residue (F82C and F82V) have also been reported in association with a RASopathy (Aoki et al., 2013; Gos et al., 2014; Kouz et al., 2016). Therefore, this variant is pathogenic.
Invitae RCV000408903 SCV000659222 pathogenic Noonan syndrome 8 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 82 of the RIT1 protein (p.Phe82Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan syndrome (PMID: 26757980). ClinVar contains an entry for this variant (Variation ID: 370035). A different variant (c.246T>G) giving rise to the same protein effect observed here (p.Phe82Leu) has been reported in many individuals affected with Noonan syndrome (PMID: 23791108, 25124994, 26242988, 26714497, 26757980, 27101134), including several de novo cases. Experimental studies for this variant have also shown that it results in increased RIT1 activity in vitro (PMID: 23791108, 24469055). In addition, a different missense substitution at this codon (p.Phe82Val) has been determined to be pathogenic (PMID: 23791108, 26757980, 25049390), suggesting that the phenylalanine residue is critical for RIT1 protein function. For these reasons, this variant has been classified as Pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn RCV000856765 SCV000999319 pathogenic Noonan syndrome 1 criteria provided, single submitter clinical testing
MVZ Praenatalmedizin und Genetik Nuernberg RCV000408903 SCV000484991 pathogenic Noonan syndrome 8 2016-12-01 no assertion criteria provided clinical testing wobble base substitution results in an already described pathogenic aminoacid substitution (rs730881014; Aoki et al., 2013) and was therefore rated pathogenic here.

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