Submissions for variant NM_005633.4(SOS1):c.2371C>A (p.Leu791Ile)

gnomAD frequency: 0.00053  dbSNP: rs142004123

Total submissions: 13

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, Mass General Brigham 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.
Eurofins Ntd Llc (ga)	RCV000038532	SCV000226115	benign	not specified	2018-09-17	criteria provided, single submitter	clinical testing
Invitae	RCV000233902	SCV000288962	likely benign	RASopathy	2024-01-29	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV001143784	SCV001304336	benign	Fibromatosis, gingival, 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813295	SCV002060643	benign	Noonan syndrome and Noonan-related syndrome	2019-06-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453284	SCV002735870	benign	Cardiovascular phenotype	2020-03-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000680310	SCV004145970	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	SOS1: BS1
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV000760994	SCV001438518	uncertain significance	Noonan syndrome		no assertion criteria provided	clinical testing