Submissions for variant NM_006939.4(SOS2):c.2014C>A (p.Leu672Ile)

gnomAD frequency: 0.00561  dbSNP: rs34139502

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513866	SCV000610577	likely benign	not provided	2017-06-20	criteria provided, single submitter	clinical testing
Invitae	RCV001081985	SCV000656011	benign	Noonan syndrome 9	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000513866	SCV000698738	benign	not provided	2017-04-12	criteria provided, single submitter	clinical testing	Variant summary: The SOS2 c.2014C>A (p.Leu672Ile) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the Ras guanine nucleotide exchange factor domain and Ras-like guanine nucleotide exchange factor domain, N-terminal (InterPro). 4/5 in silico tools predict a benign outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0019927 (208/104380 control chromosomes [3 homozygotes] in all populations), but was primarily observed in the African subpopulation at a frequency of 0.020296 (189/9312 controls chromosomes [3 homozygotes]). This frequency is about 8118 times the estimated maximal expected allele frequency of a pathogenic SOS2 variant (0.0000025), which provides strong evidence that this is likely a benign polymorphism found primarily in populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
GeneDx	RCV000612567	SCV000715216	benign	not specified	2017-06-15	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	RCV001081985	SCV001477732	likely benign	Noonan syndrome 9	2023-11-29	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001081985	SCV002763058	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159656	SCV003911933	likely benign	Cardiovascular phenotype	2022-12-29	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.