ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.899G>A (p.Arg300Gln) (rs754374236)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000800167 SCV001192881 likely benign Rasopathy 2019-12-05 reviewed by expert panel curation The c.899G>A (p.Arg300Gln) variant in SOS1 is present in 0.01% (3/30610) South Asian alleles in gnomAD. Computational prediction tools and conservation analysis suggest that this variant does not impact the protein (BP4). This variant has been identified in 5 probands with an alternate molecular basis for disease (BP5: SCV000430444.2; SCV000430443.2; SCV000730061.1; SCV000939867.1). In summary, the clinical significance of the p.Arg300Gln variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4, BP5.
Illumina Clinical Services Laboratory,Illumina RCV000307592 SCV000430443 uncertain significance Gingival fibromatosis 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000362251 SCV000430444 uncertain significance Noonan syndrome 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000606984 SCV000730061 likely benign not specified 2018-02-15 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000800167 SCV000939867 uncertain significance Rasopathy 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 300 of the SOS1 protein (p.Arg300Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs754374236, ExAC 0.006%). This variant has not been reported in the literature in individuals with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 336021). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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