Submissions for variant NM_006939.4(SOS2):c.1344G>A (p.Leu448=)

gnomAD frequency: 0.00350  dbSNP: rs35530861

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588482	SCV000531907	benign	not provided	2016-10-07	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084699	SCV000656008	benign	Noonan syndrome 9	2024-01-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588482	SCV000698736	benign	not provided	2017-04-12	criteria provided, single submitter	clinical testing	Variant summary: The SOS2 c.1344G>A (p.Leu448Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 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. The variant of interest has been found in a large, broad control population, ExAC in 507/121406 control chromosomes (3 homozygotes) at a frequency of 0.0041761, which is approximately 1670 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications but is cited as "Benign" by reputable database. Taken together, this variant is classified as benign.
Ambry Genetics	RCV002379364	SCV002695091	benign	Cardiovascular phenotype	2019-09-27	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001084699	SCV002763082	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588482	SCV002822134	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	SOS2: BP4, BP7, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001084699	SCV004564140	benign	Noonan syndrome 9	2023-10-02	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001706637	SCV001922251	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588482	SCV001955398	likely benign	not provided		no assertion criteria provided	clinical testing