Submissions for variant NM_005633.4(SOS1):c.3697C>A (p.Leu1233Ile)

gnomAD frequency: 0.00003  dbSNP: rs777373438

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000371601	SCV000330447	uncertain significance	not provided	2016-04-25	criteria provided, single submitter	clinical testing	The L1233I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the L1233I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution does occur at a position that is conserved across species. Finally, 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 pathogenic or rare benign.
Invitae	RCV001859536	SCV002194312	uncertain significance	RASopathy	2021-02-14	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 280523). This variant is present in population databases (rs777373438, ExAC 0.009%). This sequence change replaces leucine with isoleucine at codon 1233 of the SOS1 protein (p.Leu1233Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine.
Genome-Nilou Lab	RCV002467706	SCV002763553	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467705	SCV002763554	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001261114	SCV001438521	likely benign	Noonan syndrome		no assertion criteria provided	clinical testing