Submissions for variant NM_006912.6(RIT1):c.247A>C (p.Thr83Pro)

dbSNP: rs869025195

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414438	SCV000491310	pathogenic	not provided	2020-03-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the T83P variant results in enhanced Elk1 levels in comparison to wild-type (Yaoita et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26757980, 23791108, 27226556, 26714497, 25959749, 27109146, 26446362)
Ambry Genetics	RCV000622399	SCV000741154	pathogenic	Inborn genetic diseases	2015-11-19	criteria provided, single submitter	clinical testing
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000856766	SCV000999320	pathogenic	Noonan syndrome 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175490	SCV001339083	pathogenic	RASopathy	2020-03-16	criteria provided, single submitter	clinical testing	Variant summary: RIT1 c.247A>C (p.Thr83Pro) results in a non-conservative amino acid change located in the small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250842 control chromosomes (gnomAD). c.247A>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (examples- Aoki_2013, Cave_2016, Kouz_2016). These data indicate that the variant may be associated with disease. In-vitro studies evaluating an impact on protein function showed that the variant results in impaired GTP-hydrolysis and increased activation as assessed by Ras-binding domain pull-down assays (Fang_2016) and higher levels of activation of Elk1 (Yaoita_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001384933	SCV001584627	pathogenic	Noonan syndrome 8	2020-05-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This missense change is located in a region of the RIT1 protein where a significant number of previously reported RIT1 missense mutations are found (PMID: 26757980, 27101134). These observations suggest that this may be a clinically significant region of the protein. This variant has been reported to affect RIT1 protein function (PMID: 27226556). This variant has been observed in individual(s) with Noonan syndrome (PMID: 23791108). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 183409). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with proline at codon 83 of the RIT1 protein (p.Thr83Pro). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and proline.
3billion	RCV001384933	SCV002058640	pathogenic	Noonan syndrome 8	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 23791108, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183409, PS1_S). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.818, 3CNET: 0.982, PP3_P). A missense variant is a common mechanism associated with Noonan syndrome 8 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV001384933	SCV004050473	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207345	SCV000211884	pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV001384933	SCV001759991	likely pathogenic	Noonan syndrome 8		no assertion criteria provided	clinical testing