Submissions for variant NM_005633.4(SOS1):c.1310T>A (p.Ile437Asn)

dbSNP: rs397517150

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377878	SCV001575325	likely pathogenic	RASopathy	2020-07-22	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with Noonan syndrome (PMID: 24451042). This sequence change replaces isoleucine with asparagine at codon 437 of the SOS1 protein (p.Ile437Asn). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency). 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 expected to disrupt SOS1 protein function. This variant disrupts the p.Ile437 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21387466, 24451042, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002384544	SCV002693615	likely pathogenic	Cardiovascular phenotype	2021-10-18	criteria provided, single submitter	clinical testing	The p.I437N variant (also known as c.1310T>A), located in coding exon 10 of the SOS1 gene, results from a T to A substitution at nucleotide position 1310. The isoleucine at codon 437 is replaced by asparagine, an amino acid with dissimilar properties, and is located in the pleckstrin homology domain. This alteration has been reported in two individuals with Noonan syndrome, including as a de novo occurrence in one case (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Lepri FR et al. BMC Med Genet, 2014 Jan;15:14). Another alteration at the same codon, p.I437T (c.1310T>C), has been detected in several unrelated individuals reported to have Noonan syndrome, including de novo occurrences in affected index cases (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Moniez S et al. Eur J Endocrinol, 2018 Dec;179:409-418; Prasad RM et al. Pediatr Blood Cancer, 2018 11;65:e27362; Yang L et al. BMC Med Genet, 2018 12;19:212; Ferriero K et al. Front Pediatr, 2020 Sep;8:515; Lazzaro G et al. Mol Genet Genomic Med, 2020 04;8:e1069). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Genome-Nilou Lab	RCV002468240	SCV002763426	likely pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing