Submissions for variant NM_005633.4(SOS1):c.829C>A (p.Pro277Thr)

dbSNP: rs1057517871

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414064	SCV000490929	uncertain significance	not specified	2015-03-18	criteria provided, single submitter	clinical testing	The P277T variant has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The P277T variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P277T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Furthermore, missense variants in nearby residues (M269T, M269R) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Baylor Genetics	RCV001331444	SCV001523486	uncertain significance	Noonan syndrome 4	2019-03-01	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001331444	SCV002763492	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467772	SCV002763493	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414064	SCV005394547	uncertain significance	not specified	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.829C>A (p.Pro277Thr) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251348 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.829C>A has been reported in the literature in one unspecified individual affected with unexplained cardiac arrest , without strong evidence for causality (example, Grondin_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35352813). ClinVar contains an entry for this variant (Variation ID: 372585). Based on the evidence outlined above, the variant was classified as uncertain significance.