Submissions for variant NM_006939.4(SOS2):c.3968C>T (p.Pro1323Leu)

dbSNP: rs886041929

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000292130	SCV000330734	uncertain significance	not provided	2018-08-31	criteria provided, single submitter	clinical testing	The P1323L variant in the SOS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This 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 P1323L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P1323L as a variant of uncertain significance
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859540	SCV002278252	uncertain significance	Noonan syndrome 9	2023-08-16	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 280784). This variant has not been reported in the literature in individuals affected with SOS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1323 of the SOS2 protein (p.Pro1323Leu).
Genome-Nilou Lab	RCV001859540	SCV002762962	uncertain significance	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004678657	SCV005170318	uncertain significance	Cardiovascular phenotype	2024-04-13	criteria provided, single submitter	clinical testing	The p.P1323L variant (also known as c.3968C>T), located in coding exon 23 of the SOS2 gene, results from a C to T substitution at nucleotide position 3968. The proline at codon 1323 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.