ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1300G>A (p.Gly434Arg) (rs397517148)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788323 SCV000927387 pathogenic not provided 2017-08-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626886 SCV000747589 pathogenic Pulmonic stenosis; Short stature; Ptosis; Abnormality of the sternum 2017-01-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781878 SCV000920259 pathogenic Rasopathy 2018-06-11 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1300G>A (p.Gly434Arg) results in a non-conservative critical amino acid change located in the membrane-binding surface of the Pleckstrin Homology (PH) domain of the encoded protein sequence (Lepri_2011). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245568 control chromosomes (gnomAD). The variant, c.1300G>A, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Alfieri_2014, Binder_2012, Lepri_2011, Roberts_2007). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, and demonstrated an increased capacity to induce ERK activation in starved cells (Smith_2013). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038514 SCV000062192 pathogenic Noonan syndrome 2012-11-13 criteria provided, single submitter clinical testing The 1300G>A (Gly434Arg) variant in SOS1 has previously been identified as a de n ovo variant in one individual with sporadic clinical features of Noonan syndrome (Zenker 2007). In addition, a different nucleotide change that causes the same amino acid change at this location (1300G>C) has also been associated with the c linical features of Noonan syndrome and was shown to have occurred de novo (Robe rts 2007). Therefore, this variant is highly likely to be pathogenic.

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