Submissions for variant NM_005633.4(SOS1):c.1558G>A (p.Asp520Asn)

gnomAD frequency: 0.00003  dbSNP: rs754115060

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000812535	SCV000952852	uncertain significance	RASopathy	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 520 of the SOS1 protein (p.Asp520Asn). This variant is present in population databases (rs754115060, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 656182). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. 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.
Ambry Genetics	RCV002397676	SCV002708864	uncertain significance	Cardiovascular phenotype	2023-04-25	criteria provided, single submitter	clinical testing	The p.D520N variant (also known as c.1558G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1558. The aspartic acid at codon 520 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002462177	SCV002756966	uncertain significance	not provided	2022-05-18	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29493581)
Genome-Nilou Lab	RCV002468063	SCV002763405	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468062	SCV002763406	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV002462177	SCV005411672	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	PP2