2-39022938-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM1 PP3 BP6_Very_Strong BS2

The NM_005633.4(SOS1):c.1490G>A(p.Arg497Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R497P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Likely benign reviewed by expert panel U:9 B:5
• Conservation: PhyloP100: 7.46

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 Benign. Variant got -9 ACMG points.

• PM1: In a domain PH (size 104) in uniprot entity SOS1_HUMAN there are 23 pathogenic changes around while only 6 benign (79%) in NM_005633.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• BP6: Variant 2-39022938-C-T is Benign according to our data. Variant chr2-39022938-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45348.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39022938-C-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1490G>A	p.Arg497Gln	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1490G>A	p.Arg497Gln	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000559 AC: 14 AN: 250470 Hom.: 0 AF XY: 0.0000738 AC XY: 10 AN XY: 135524

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461248 Hom.: 0 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 726958

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000532 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:9 Benign:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2022	Identified in an individual with Noonan syndrome who also had a de novo pathogenic variant in the RAF1 gene, likely the causative variant (Longoni et al., 2010); and identified in another individual with features of Noonan syndrome but was inherited from an asymptomatic parent (Lepri et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are commonly considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17143282, 12628188, 21387466, 29493581, 20648242, 25712082, 22585553, 24803665, 20683980, 29752777, 34426522) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 01, 2014	proposed classification - variant undergoing re-assessment, contact laboratory -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2020	Variant summary: SOS1 c.1490G>A (p.Arg497Gln) results in a conservative amino acid change located in the Pleckstrin homology domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 250470 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. c.1490G>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (e.g. Lepri_2011, Longoni_2010). In one family the variant was indicated to have been inherited from an unaffected parent (Lepri_2011). A similar inheritance from a carrier mother has been observed at-least once at our laboratory. In another family, the variant co-occurred in a patient with a de novo pathogenic RAF1 variant (c.781C>T, p.Pro261Ser). The patient's father and paternal grandfather also carried the variant of interest and authors indicated that the variant may have contributed to cutaneous anomalies that were observed in these family members (Longoni_2010). Another study (Rodriguez_2018) reported the variant in a patient affected with isolated cryptorchidism. Experimental evidence evaluating an impact on protein function demonstrated the variant does not induce Erk1 phosphorylation above the level of the wild type. Evaluating Rac1 pathway signal transduction, the authors determined the variant activates Jnk however, the implications of this finding in disease-manifestation are not conclusively established especially given that Jnk was not significantly activated under EGF stimulation in cells transfected with the known pathogenic p.M269R variant (Longoni_2010). Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. However, recently the ClinGen RASopathy Variant Curation Expert Panel settled on a classification of this variant as Likely Benign (personal communication, June 2020). Based on the evidence outlined above, the variant was re-classified as likely benign. -

Noonan syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Sep 23, 2020	The c.1490G>A missense variant has a frequency of 0.00005677 (16 of 281,850 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0001130 (4 of 35,392) in the Latino subpopulation (http://gnomad.broadinstitute.org). Although multiple lines of computational evidence suggest a deleterious effect on the gene or gene product (PP3), in vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). This variant has been observed in one proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). This variant has been classified as likely benign by the ClinGen RASopathy Variant Curation Expert Panel with additional unpublished patient data (SCV001424738.1). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BS3, BP5. -
Uncertain significance, no assertion criteria provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 19, 2013	- -

RASopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 20, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 497 of the SOS1 protein (p.Arg497Gln). This variant is present in population databases (rs371314838, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Noonan syndrome (PMID: 20683980, 21387466). ClinVar contains an entry for this variant (Variation ID: 45348). 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) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SOS1 function (PMID: 20683980, 25712082). 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. -
Likely benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Jul 02, 2020	The c.1490G>A (p.Arg497Gln) variant in SOS1 was present in 0.0113% (4/35392) of Latino chromosomes in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in 1 proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). Of note, it has also been observed in other probands with disparate phenotypes and their reportedly unaffected parents; however, these individuals were not well-phenotyped and, therefore, do not meet current requirements for BS2 (BS2 not met; PMID:21387466, Otto von Guericke University Magdeburg, GeneDx, Partners Laboratory for Molecular Medicine, Integrated Genetics, and Baylor Genetics internal data; ClinVar SCV000209114.12, SCV000062197.7, SCV001361139.1). In vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). Although this variant occurs in a location defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1, expert judgement was used to classify this variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): BS3, BP5. -

Noonan syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Noonan syndrome 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2021

The p.R497Q variant (also known as c.1490G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1490. The arginine at codon 497 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a proband with Noonan syndrome who also had a de novo mutation in the RAF1 gene, and ectodermal findings atypical for RAF1 mutations. The proband's father and paternal grandfather, who also had the p.R497Q variant, were reported to not have Noonan syndrome; however, they displayed similar mild ectodermal findings (Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). This variant was also detected in an individual from a cohort with Noonan syndrome or related features where it was inherited from a reportedly unaffected parent, and in an individual with cryptorchidism; however, details were limited (Lepri F et al. Hum. Mutat., 2011 Jul;32:760-72; Rodríguez F et al. Andrology, 2018 07;6:579-584). Functional assays have indicated this variant to result in activation of the Rac1 pathway, but not of the Ras-Erk pathway (Longoni M et al. Am. J. Med. Genet. A, 2010 Sep;152A:2176-84). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Fibromatosis, gingival, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 29, 2022

- -

Noonan syndrome and Noonan-related syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Pathogenic	3.1	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0040	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.87
MVP		0.90
MPC		1.6
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.73
gMVP		0.62

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: rs371314838; hg19: chr2-39250079; COSMIC: COSV67676453; COSMIC: COSV67676453;