ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1018C>T (p.Pro340Ser) (rs190222208)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000788014 SCV000927046 benign Noonan syndrome and Noonan-related syndrome 2019-06-27 reviewed by expert panel curation The c.1018C>T (p.Pro340Ser) variant in the SOS1 gene has been found not to segregate in a family member of a patient who underwent testing for RASopathies as well as another adult who was unaffected (BS4; GeneDx, Invitae internal data; GTR Lab ID: 26957, 500031; SCV000514724.5, SCV000659124.2). This variant has also been identified in a patient with an alternate molecular basis of disease (BP5; PMID 22585553). The filtering allele frequency of the p.Pro340Ser variant is 0.022% for East Asian exomes in the gnomAD database (20/251276 with 95% CI), which is high enough frequency to be considered strong evidence for the variant being benign by the ClinGen RASopathy Expert Panel (BS1). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5, BS1.
GeneDx RCV000588783 SCV000514724 likely benign not provided 2017-08-16 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 RCV000536024 SCV000659124 uncertain significance Rasopathy 2019-06-09 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 340 of the SOS1 protein (p.Pro340Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs190222208, ExAC 0.06%). This variant has been reported in an individual affected with Noonan syndrome who also carried a pathogenic variant in the PTPN11 gene (PMID: 22585553). ClinVar contains an entry for this variant (Variation ID: 40664). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Integrated Genetics/Laboratory Corporation of America RCV000588783 SCV000698610 likely benign not provided 2016-01-12 criteria provided, single submitter clinical testing Variant summary: The c.1018C>T variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ser. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant has been reported in one patient with co-occurrence of PTPN11 c.1403C>T/p.T468M (pathogenic, Fahrner_2012). This variant is found in 14/119120 control chromosomes at a frequency of 0.0001175, which is about 4 times of maximal expected frequency of a pathogenic allele (0.00003), suggesting this variant is benign. Taken together, this variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV001136600 SCV001296454 uncertain significance Noonan syndrome 4 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV001142374 SCV001302809 benign Gingival fibromatosis 1 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

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