Submissions for variant NM_005633.4(SOS1):c.1720G>A (p.Val574Ile)

gnomAD frequency: 0.00004  dbSNP: rs727504641

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155902	SCV000205613	uncertain significance	not specified	2013-06-24	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Val574Ile varia nt in SOS1 has not been previously identified by our laboratory, nor has it been reported in the literature. In addition, this variant is absent in large popula tion studies. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact t he protein, though this information is not predictive enough to rule out pathoge nicity. In summary, additional information is needed to fully assess the clinica l significance of the Val574Ile variant.
Illumina Laboratory Services, Illumina	RCV000376698	SCV000430433	uncertain significance	Fibromatosis, gingival, 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000284494	SCV000430434	uncertain significance	Noonan syndrome 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000586070	SCV000490824	uncertain significance	not provided	2016-12-21	criteria provided, single submitter	clinical testing	The V574I variant has not been published as a pathogenic or as a benign variant to our knowledge. The V574I variant 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. This substitution occurs at a position that is conserved in mammals. However, the V574I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense pathogenic variants in nearby residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586070	SCV000698617	uncertain significance	not provided	2016-11-21	criteria provided, single submitter	clinical testing	Variant summary: The SOS1 c.1720G>A (p.Val574Ile) variant causes a missense change involving the alteration of a conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121360 (1/30339), predominantly in the European (Non-Finnish) cohort, 4/66722 (1/16680), which exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333, therefore, suggesting this variant is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. However, this observation does not need to be cautiously considered since the cohort does harbor individuals that could have a SOS1 phenotype. A clinical diagnostic laboratory cites the variant as "uncertain significance." However, the variant has not been reported, to our knowledge, in affected individuals via publications. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign."
Invitae	RCV000654926	SCV000776832	likely benign	RASopathy	2023-08-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764405	SCV000895462	uncertain significance	Fibromatosis, gingival, 1; Noonan syndrome 4	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000284494	SCV002763377	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000376698	SCV002763378	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298167	SCV003998988	uncertain significance	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The p.V574I variant (also known as c.1720G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1720. The valine at codon 574 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a limb girdle muscular dystrophy cohort (Fichna JP et al. Hum Genomics, 2018 Jul;12:34). This alteration has also been reported in a cohort of subjects referred for genetic testing for Noonan syndrome (Leach NT et al. Genet Med, 2019 Feb;21:417-425). 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.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV003448272	SCV004175706	uncertain significance	Brugada syndrome	2023-08-29	criteria provided, single submitter	clinical testing	Heterozygous variant NM_005633:c.1720G>A (p.Val574Ile) in the SOS1 gene was found on WES data in female proband (52 y.o., Caucasian) with Brugada-like ECG, and family history burdened with oncology (no precise data about site and histology available). No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00003985 (Date of access 29-08-2023). Clinvar contains entry for this variant (Variation ID: 179117). This variant has been reported on WES data in 1 patient with limb girdle muscular dystrophy (PMID: 29970176) and in prenatal cohort for genetic testing for Noonan syndrome (PMID: 29907801). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) wtih following criteria selected: BP4.