Submissions for variant NM_006912.6(RIT1):c.229G>T (p.Ala77Ser)

dbSNP: rs869025191

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000680952	SCV000808401	pathogenic	not provided	2019-03-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; A77S confers a gain-of-function by causing significant increase in Elk1 activation in comparison to wild-type (Yaoita et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26714497, 27109146, 29734338, 24469055)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861885	SCV002247029	pathogenic	Noonan syndrome 8	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 77 of the RIT1 protein (p.Ala77Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala77 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26714497, 26757980, 27101134, 29402968). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 561621). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26714497; Invitae). This variant is not present in population databases (ExAC no frequency).
3billion	RCV001861885	SCV002318453	pathogenic	Noonan syndrome 8	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported to be associated with RIT1 related disorder (ClinVar ID: VCV000561621, PMID:26714497). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26714497). Different missense change at the same codon have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000183403, VCV000228289, VCV000850519, PMID:25049390, 26714497). It is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.809>=0.6, 3CNET: 0.994>=0.75). Missense changes are a common disease-causing mechanism. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab	RCV001861885	SCV004050488	pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Molecular Genetics, Centre for Human Genetics	RCV003453398	SCV004190093	pathogenic	Noonan syndrome 1		no assertion criteria provided	clinical testing