Submissions for variant NM_005633.4(SOS1):c.3391+7A>G

gnomAD frequency: 0.00066  dbSNP: rs201982464

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000228908	SCV000616506	benign	RASopathy	2017-04-18	reviewed by expert panel	curation	The filtering allele frequency of the c.3391+7A>G variant in the SOS1 gene is 0.193% (41/16108) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038550	SCV000062228	benign	not specified	2015-12-22	criteria provided, single submitter	clinical testing	c.3391+7A>G in intron 21 of SOS1: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.3% (41/16108) of South Asian chromosomes including one homozygous individual and 0.07% (45/65182) European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201982464).
GeneDx	RCV000038550	SCV000171780	benign	not specified	2013-03-14	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590714	SCV000206729	likely benign	not provided	2023-10-23	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000590714	SCV000227827	uncertain significance	not provided	2015-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228908	SCV000288966	benign	RASopathy	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000038550	SCV000311203	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094707	SCV000430419	likely benign	Noonan syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000300498	SCV000430420	benign	Fibromatosis, gingival, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590714	SCV000698634	benign	not provided	2017-07-24	criteria provided, single submitter	clinical testing	Variant summary: The SOS1 c.3391+7A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 94/118614 control chromosomes (1 homozygote) at a frequency of 0.0007925, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003), suggesting this variant is likely a benign polymorphism. Ths variant has been reported in affected individual and reported as a "disease-unrelated variant" by authors (Lepri_2011). In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as benign/VUS. Taken together, this variant is classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813358	SCV002060653	likely benign	Noonan syndrome and Noonan-related syndrome	2021-06-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000038550	SCV002070898	benign	not specified	2019-05-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590714	SCV004145966	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	SOS1: BS1
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000590714	SCV001808705	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590714	SCV001926874	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590714	SCV001970243	likely benign	not provided		no assertion criteria provided	clinical testing