Submissions for variant NM_005633.4(SOS1):c.2489A>G (p.Asn830Ser)

gnomAD frequency: 0.00001  dbSNP: rs397517158

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159131	SCV000209075	uncertain significance	not provided	2021-03-08	criteria provided, single submitter	clinical testing	Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556321	SCV000659137	uncertain significance	RASopathy	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 830 of the SOS1 protein (p.Asn830Ser). This variant is present in population databases (rs397517158, gnomAD 0.002%). 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: 181538). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781876	SCV000920255	uncertain significance	not specified	2018-02-12	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.2489A>G (p.Asn830Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 121166 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions (1.7e-05 vs 3e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2489A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198588	SCV001369578	uncertain significance	Fibromatosis, gingival, 1	2019-10-11	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP1,PP3,PP4.
Genome-Nilou Lab	RCV002467624	SCV002763299	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001198588	SCV002763300	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000159131	SCV005187624	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003398819	SCV004121234	uncertain significance	SOS1-related disorder	2024-02-13	no assertion criteria provided	clinical testing	The SOS1 c.2489A>G variant is predicted to result in the amino acid substitution p.Asn830Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.