Submissions for variant NM_005633.4(SOS1):c.3357C>T (p.Thr1119=)

gnomAD frequency: 0.00011  dbSNP: rs373319212

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038548	SCV000062226	likely benign	not specified	2015-10-16	criteria provided, single submitter	clinical testing	p.Thr1119Thr in exon 21 of SOS1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 8/65198 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs373319212).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588706	SCV000698633	benign	not provided	2016-05-23	criteria provided, single submitter	clinical testing	Variant summary: The SOS1 c.3357C>T (p.Thr1119Thr) variant causes a synonymous change involving a conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing and ESE finder predicting that this variant may create a new affect ESE site of, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 9/118630 (1/13175, frequency: 0.0000759), predominantly in the European (Non-Finnish) cohort, 8/65198 (1/8149), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333 (0.00003). Therefore, suggesting that the variant is a common polymorphism found in population(s) of European (Non-Finnish) origin. A publication cites the variant to have been found in at least one affected individual, although with limited information (ie lack of co-occurrence cosegregation data). In addition, a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081903	SCV001003690	likely benign	RASopathy	2025-01-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000588706	SCV001859901	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321514	SCV002606272	likely benign	Cardiovascular phenotype	2020-03-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Genome-Nilou Lab	RCV002467550	SCV002763225	likely benign	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467549	SCV002763226	likely benign	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002482997	SCV002803217	likely benign	Fibromatosis, gingival, 1; Noonan syndrome 4	2021-08-20	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588706	SCV005876280	likely benign	not provided	2023-12-15	criteria provided, single submitter	clinical testing