ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.1370A>G (p.His457Arg)

dbSNP: rs1060503524
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000474019 SCV000553264 uncertain significance RASopathy 2016-09-27 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SOS1-related disease. This sequence change replaces histidine with arginine at codon 457 of the SOS1 protein (p.His457Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174555 SCV001337715 uncertain significance not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1370A>G (p.His457Arg) results in a non-conservative amino acid change located in the Pleckstrin homology domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251106 control chromosomes (gnomAD). 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.1370A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab RCV002467819 SCV002763416 uncertain significance Noonan syndrome 4 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467818 SCV002763417 uncertain significance Fibromatosis, gingival, 1 criteria provided, single submitter clinical testing

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