ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2371C>A (p.Leu791Ile) (rs142004123)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000233902 SCV000616439 benign Rasopathy 2017-04-03 reviewed by expert panel curation The filtering allele frequency of the c.2371C>A (p.Leu791Ile) variant in the SOS1 gene is 0.081% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (67/66688 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038532 SCV000062210 likely benign not specified 2015-06-05 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000680310 SCV000209073 benign not provided 2016-06-06 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000038532 SCV000226115 benign not specified 2018-09-17 criteria provided, single submitter clinical testing
Invitae RCV000233902 SCV000288962 likely benign Rasopathy 2020-09-01 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000760994 SCV000890909 benign Noonan syndrome 2020-09-23 criteria provided, single submitter clinical testing The c.2371C>A missense variant has a frequency of 0.0005737 (162 of 282,368 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0009786 (126 of 128,756) in the European non-Finnish population (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1). In silico tools are not in agreement regarding the effect of this variant on protein function and functional assays have not been performed. This variant has been classified as benign by the ClinGen RASopathy Variant Curation Expert Panel (SCV000616439.3). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BA1.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000038532 SCV000920257 benign not specified 2017-09-05 criteria provided, single submitter clinical testing Variant summary: The SOS1 c.2371C>A (p.Leu791Ile) variant located in the Ras guanine nucleotide exchange factor domain (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 153/276674 control chromosomes at a frequency of 0.000553, which is approximately 18 times the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003), suggesting this variant is likely a benign polymorphism. A publication, Lepri_2014, cites the variant in 2 individuals with limited information (ie, lack of cosegregation and/or co-occurrence data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001138721 SCV001298796 uncertain significance Noonan syndrome 4 2017-04-27 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 RCV001143784 SCV001304336 benign Gingival fibromatosis 1 2017-04-27 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.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000760994 SCV001438518 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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