ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1720G>A (p.Val574Ile) (rs727504641)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764405 SCV000895462 uncertain significance Gingival fibromatosis 1; Noonan syndrome 4 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000586070 SCV000490824 uncertain significance not provided 2016-12-21 criteria provided, single submitter clinical testing The V574I variant has not been published as a pathogenic or as a benign variant to our knowledge. The V574I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. However, the V574I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense pathogenic variants in nearby residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Illumina Clinical Services Laboratory,Illumina RCV000376698 SCV000430433 uncertain significance Gingival fibromatosis 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000284494 SCV000430434 uncertain significance Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586070 SCV000698617 uncertain significance not provided 2016-11-21 criteria provided, single submitter clinical testing Variant summary: The SOS1 c.1720G>A (p.Val574Ile) variant causes a missense change involving the alteration of a conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121360 (1/30339), predominantly in the European (Non-Finnish) cohort, 4/66722 (1/16680), which exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333, therefore, suggesting this variant is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. However, this observation does not need to be cautiously considered since the cohort does harbor individuals that could have a SOS1 phenotype. A clinical diagnostic laboratory cites the variant as "uncertain significance." However, the variant has not been reported, to our knowledge, in affected individuals via publications. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae RCV000654926 SCV000776832 uncertain significance Rasopathy 2018-01-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 574 of the SOS1 protein (p.Val574Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs727504641, ExAC 0.006%). This variant has not been reported in the literature in individuals with SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 179117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000155902 SCV000205613 uncertain significance not specified 2013-06-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Val574Ile varia nt in SOS1 has not been previously identified by our laboratory, nor has it been reported in the literature. In addition, this variant is absent in large popula tion studies. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact t he protein, though this information is not predictive enough to rule out pathoge nicity. In summary, additional information is needed to fully assess the clinica l significance of the Val574Ile variant.

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