rs727504641

chr2-39022708-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_005633.4(SOS1):c.1720G>A(p.Val574Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:1
• Conservation: PhyloP100: 3.58

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13134071).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1720G>A	p.Val574Ile	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1720G>A	p.Val574Ile	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 250960 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461576 Hom.: 1 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Noonan syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2016	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." -

Fibromatosis, gingival, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2013

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. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations

Aug 29, 2023

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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2023

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. -

RASopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	19
Dann	Benign	0.59
DEOGEN2	Benign	0.34	T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.030	N;N;N
REVEL	Benign	0.034
Sift	Benign	0.63	T;T;T
Sift4G	Benign	0.90	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.23
MVP		0.28
MPC		0.45
ClinPred		0.065	T
GERP RS		3.9
Varity_R		0.085
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504641; hg19: chr2-39249849;