Submissions for variant NM_006912.6(RIT1):c.67A>C (p.Lys23Gln)

dbSNP: rs869312687

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000209835	SCV000265566	pathogenic	Noonan syndrome 8	2015-06-09	criteria provided, single submitter	research
GeneDx	RCV000680368	SCV000621095	likely pathogenic	not provided	2019-12-18	criteria provided, single submitter	clinical testing	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: 26518681, 28554332)
Invitae	RCV000209835	SCV000659224	pathogenic	Noonan syndrome 8	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 23 of the RIT1 protein (p.Lys23Gln). 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: 28554332; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 224122). 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. This variant disrupts the p.Lys23 amino acid residue in RIT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26518681, 27101134, 29734338; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000521893	SCV000731275	uncertain significance	not specified	2016-11-15	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Lys40Gln variant in RIT1 has not been previously reported in individuals with clinical fe atures of a RASopathy and is absent from large population studies. However, anot her variant at the same position (p.Lys40Asn; reported as p.Lys23Asn on NM_00691 2.5) was identified as a de novo variant in 1 individual with Noonan syndrome (N emcikova 2015), suggesting changes at this position are not tolerated. Computati onal prediction tools and conservation analysis suggest that the p.Lys40Gln vari ant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathoge nic role, the clinical significance of the p.Lys40Gln variant is uncertain.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626786	SCV000747489	likely pathogenic	Hypertelorism; Short stature; Downslanted palpebral fissures; Pedal edema	2017-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003372654	SCV004096820	likely pathogenic	Cardiovascular phenotype	2023-08-09	criteria provided, single submitter	clinical testing	The p.K23Q variant (also known as c.67A>C), located in coding exon 1 of the RIT1 gene, results from an A to C substitution at nucleotide position 67. The lysine at codon 23 is replaced by glutamine, an amino acid with similar properties. This variant has been detected in individuals with features consistent with Noonan syndrome, including a de novo occurrence (Bowling KM et al. Genome Med, 2017 May;9:43; external 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, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.