Submissions for variant NM_006912.6(RIT1):c.251C>T (p.Ala84Val)

gnomAD frequency: 0.00001  dbSNP: rs869025196

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000492853	SCV000583365	likely pathogenic	not provided	2017-06-01	criteria provided, single submitter	clinical testing	The A84V variant has been published previously in association with Noonan syndrome (Cavé et al., 2016). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). A84V 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. Missense variants in nearby residues (E81G, F82V/S/L, T83P, Y89H) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000207351	SCV000713165	likely pathogenic	Noonan syndrome	2017-04-07	criteria provided, single submitter	clinical testing	The p.Ala101Val variant (reported as p.Ala84Val on transcript NM_006912.5) in RI T1 has been reported in 1 individual with clinical features of Noonan syndrome a nd segregated in 2 affected relatives from 1 family (Cave 2016). This variant is absent from large population studies. This variant has been reported in ClinVar (Variation ID 183410). Computational prediction tools and conservation analysis suggest that the p.Ala101Val variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, th e p.Ala101Val variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384932	SCV001584626	pathogenic	Noonan syndrome 8	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 84 of the RIT1 protein (p.Ala84Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 26757980; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183410). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV003162683	SCV003860440	likely pathogenic	Cardiovascular phenotype	2023-02-06	criteria provided, single submitter	clinical testing	The p.A84V variant (also known as c.251C>T), located in coding exon 4 of the RIT1 gene, results from a C to T substitution at nucleotide position 251. The alanine at codon 84 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a family with features of Noonan syndrome (Cavé H et al. Eur J Hum Genet, 2016 Aug;24:1124-31). The variant has also been detected in multiple unrelated individuals with RASopathy at other clinical laboratories (Invitae, personal communication; GeneDx, personal communication; Laboratory for Molecular Medicine, personal communication). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome-Nilou Lab	RCV001384932	SCV004050472	likely pathogenic	Noonan syndrome 8	2023-04-11	criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000207351	SCV000211885	likely pathogenic	Noonan syndrome		no assertion criteria provided	clinical testing