Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV001044625 | SCV001208430 | uncertain significance | Noonan syndrome 8 | 2024-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 47 of the RIT1 protein (p.Pro47Leu). This variant is present in population databases (rs747376042, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RIT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 842237). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt RIT1 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001175489 | SCV001339082 | uncertain significance | not specified | 2020-03-16 | criteria provided, single submitter | clinical testing | Variant summary: RIT1 c.140C>T (p.Pro47Leu) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.140C>T in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
St. |
RCV001044625 | SCV002584757 | uncertain significance | Noonan syndrome 8 | 2022-07-21 | criteria provided, single submitter | clinical testing | The RIT1 c.140CT (p.Pro47Leu) missense change has a maximum subpopulation frequency of 0.0039% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant occurs in a gene where missense variants are a common mechanism of disease (PP2). To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Ambry Genetics | RCV002393220 | SCV002697844 | uncertain significance | Cardiovascular phenotype | 2022-11-22 | criteria provided, single submitter | clinical testing | The p.P47L variant (also known as c.140C>T), located in coding exon 2 of the RIT1 gene, results from a C to T substitution at nucleotide position 140. The proline at codon 47 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV001044625 | SCV002801306 | uncertain significance | Noonan syndrome 8 | 2022-02-11 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV001044625 | SCV004050497 | uncertain significance | Noonan syndrome 8 | 2023-04-11 | criteria provided, single submitter | clinical testing |