Submissions for variant NM_005633.4(SOS1):c.1666G>A (p.Val556Ile)

dbSNP: rs753909912

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV001172274	SCV001335314	uncertain significance	RASopathy	2020-03-09	reviewed by expert panel	curation	The c.1666G>A (p.Val556Ile) variant in SOS1 was present in 0.005437% (1/18392) of East Asian alleles in gnomAD v2.1.1 and was absent from v3. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 31219622; GeneDx internal data, SCV000808076.1; Invitae internal data; BC Children’s Hospital internal data). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2.
GeneDx	RCV000680632	SCV000808076	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing	The V556I variant of uncertain significance in the SOS1 gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, V556I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001172274	SCV001545952	uncertain significance	RASopathy	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 556 of the SOS1 protein (p.Val556Ile). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 31219622). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 561347). 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	RCV003303103	SCV004002693	uncertain significance	Cardiovascular phenotype	2023-05-02	criteria provided, single submitter	clinical testing	The p.V556I variant (also known as c.1666G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1666. The valine at codon 556 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been detected and reported as de novo in an individual from a cohort of patients with features of Noonan syndrome; however, details were limited (Li X et al. Clin Genet, 2019 Oct;96:290-299). This amino acid position is not well 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.