Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001193590 | SCV001362520 | benign | not specified | 2019-12-16 | criteria provided, single submitter | clinical testing | Variant summary: RRAS c.563G>A (p.Arg188Gln) results in a conservative amino acid change in 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 0.00015 in 246938 control chromosomes. The observed variant frequency is approximately 60 fold of the estimated maximal expected allele frequency for a pathogenic variant in RRAS causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.563G>A 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 benign. |
Labcorp Genetics |
RCV001863059 | SCV002288263 | uncertain significance | Noonan syndrome | 2023-09-04 | criteria provided, single submitter | clinical testing | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 928936). This variant has not been reported in the literature in individuals affected with RRAS-related conditions. This variant is present in population databases (rs374621936, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 188 of the RRAS protein (p.Arg188Gln). |
St. |
RCV001863059 | SCV003928043 | uncertain significance | Noonan syndrome | 2023-03-16 | criteria provided, single submitter | clinical testing | The RRAS c.563G>A (p.Arg188Gln) missense change has a maximum subpopulation frequency of 0.025% 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. 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 | RCV001193590 | SCV005016136 | uncertain significance | not specified | 2023-01-06 | criteria provided, single submitter | clinical testing | The c.563G>A (p.R188Q) alteration is located in exon 5 (coding exon 5) of the RRAS gene. This alteration results from a G to A substitution at nucleotide position 563, causing the arginine (R) at amino acid position 188 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Prevention |
RCV003945910 | SCV004759739 | uncertain significance | RRAS-related disorder | 2023-11-29 | no assertion criteria provided | clinical testing | The RRAS c.563G>A variant is predicted to result in the amino acid substitution p.Arg188Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be an undocumented cause of disease (Gelb et al. 2018. PubMed ID 29493581). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |