ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.749T>C (p.Val250Ala) (rs139290271)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000157705 SCV000884561 uncertain significance not provided 2017-12-22 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.
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).
GeneDx RCV000157705 SCV000209099 likely benign not provided 2017-07-14 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.
Greenwood Genetic Center Diagnostic Laboratories,Greenwood Genetic Center RCV000157705 SCV000207694 uncertain significance not provided 2015-01-15 no assertion criteria provided clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000228572 SCV000288969 likely benign Rasopathy 2017-11-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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.
Molecular Diagnostics Lab,Nemours Alfred I. duPont Hospital for Children RCV000038569 SCV000263041 uncertain significance not specified 2015-07-21 criteria provided, single submitter clinical testing

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