ClinVar Miner

Submissions for variant NM_006912.6(RIT1):c.67A>C (p.Lys23Gln) (rs869312687)

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Total submissions: 5
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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 uncertain significance not provided 2017-09-19 criteria provided, single submitter clinical testing The K23Q variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The K23Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The X#X variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000209835 SCV000659224 uncertain significance Noonan syndrome 8 2017-03-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 23 of the RIT1 protein (p.Lys23Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RIT1-related disease. ClinVar contains an entry for this variant (Variation ID: 224122). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare 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; Edema of the lower limbs 2017-01-01 criteria provided, single submitter clinical testing

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