Submissions for variant NM_005633.4(SOS1):c.749T>C (p.Val250Ala)

gnomAD frequency: 0.00054  dbSNP: rs139290271

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000228572	SCV000616434	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The filtering allele frequency of the c.749T>C (p.Val250Ala) variant in the SOS1 gene is 0.089% for African chromosomes by the Exome Aggregation Consortium (15/10392 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	RCV000038569	SCV000062247	uncertain significance	not specified	2011-06-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val250Ala varia nt has not been previously reported in the literature. However, this variant was identified in one other Black individual tested by our laboratory and that indi vidual's reportedly unaffected mother. This variant has now been identified in 2 /75 (2.7%) of Black probands tested by our laboratory. In addition, Val at posit ion 250 is not conserved across evolutionarily distinct species and computationa l analyses (PolyPhen2, SIFT, AlignGVGD) predict that this variant will not impac t the normal function of the protein. It should be noted that the sensitivity an d specificity of these computational programs has not been determined by our lab oratory. Therefore, the clinical significance of this variant cannot be determin ed conclusively at this time; however, based upon the arguments described above we would lean towards a more likely benign role.
GeneDx	RCV000157705	SCV000209099	benign	not provided	2019-10-25	criteria provided, single submitter	clinical testing
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000038569	SCV000263041	uncertain significance	not specified	2015-07-21	criteria provided, single submitter	clinical testing
Invitae	RCV000228572	SCV000288969	likely benign	RASopathy	2024-01-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000157705	SCV000511122	likely benign	not provided	2016-10-11	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038569	SCV000698645	likely benign	not specified	2018-05-13	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.749T>C (p.Val250Ala) results in a non-conservative amino acid change located in the Dbl homology (DH) domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 277018 control chromosomes. The observed variant frequency is approximately 6 fold above the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.749T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including uncertain significance (2x), likely benign (3x), and benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000157705	SCV000884561	uncertain significance	not provided	2017-12-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813282	SCV002060905	uncertain significance	Noonan syndrome and Noonan-related syndrome	2016-12-12	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390135	SCV002675055	benign	Cardiovascular phenotype	2019-03-28	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.
PreventionGenetics, part of Exact Sciences	RCV003944869	SCV004760752	likely benign	SOS1-related condition	2019-11-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000157705	SCV000207694	uncertain significance	not provided	2015-01-15	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261072	SCV001438474	likely benign	Noonan syndrome		no assertion criteria provided	clinical testing