2-39022773-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS2PM2PP3PP2PS3PS4PM1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1655G>A (p.Arg552Lys) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837, 17143282, 30266093, 26686981). This variant has been detected in at least 7 independent occurrences with clinical features of a RASopathy (PS4; PMIDs: 17586837, 22420426, 28378436, 29037749, 25337068, 21387466, 21784453, 26918529, 21274610). In vitro functional studies provide some evidence that the p.Arg552Lys variant may impact protein function (PS3; PMID:21784453). This residue has been defined as a PM1 hotspot by the RAS VCEP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg552Lys variant may impact the protein (PP3). 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 missense variants are common (PP2; PMID:29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1_Strong, PM2, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261726/MONDO:0018997/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:18

Conservation

PhyloP100: 7.80

Variant links:

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]

SOS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS2

For more information check the summary or visit ClinGen Evidence Repository.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.1655G>A	p.Arg552Lys	missense_variant	Exon 10 of 23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 link	c.1655G>A	p.Arg552Lys	missense_variant	Exon 10 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727092

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Noonan syndrome 4

Pathogenic:5

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 20, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at position 1655 of the coding sequence of the SOS1 gene that results in an arginine to lysine amino acid change at residue 552 of the SOS Ras/Rac guanine nucleotide exchange factor 1 protein. The 552 residue falls in the PH-Rem linker domain (PMID: 17143282) which plays a critical role in SOS Ras/Rac guanine nucleotide exchange factor 1's function. This is a previously reported variant (ClinVar 40683) that has been determined to be pathogenic by an expert panel (ClinGen RASopathy Variant Curation Expert Panel SCV000927028.1) and has been observed in individuals affected by RASopathy syndrome, Noonan syndrome, or intellectual disability (PMID: 38572385, 35390071, 33128510, 31573083, 17586837, 17143282, 30266093, 26686981, 22420426, 28378436, 29037749, 25337068, 21387466). This variant is present in 1 of 1613738 alleles (0.00006%) in the gnomAD v4.1.0 population dataset. Multiple bioinformatic tools predict that this arginine to lysine amino acid change would be damaging, and the Arg552 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant show this variant may impact the protein function (PMID: 21784453). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM1, PM2, PP2, PP3, PS2, PS3, PS4 -

Jul 09, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2021

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 4 (MIM#610733). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Due to ascertainment bias and variable expressivity with frequent subtlety of features, the penetrance of Noonan syndrome is difficult to determine; affected adults are often diagnosed only after the diagnosis of a more severely affected child (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Three alternative amino acid changes at the same position have been observed in gnomAD (v2 and v3) (same allele frequency in all: 1 heterozygote, 0 homozygote). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0701 - Multiple missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple missense changes at this amino acid have been reported in ClinVar as pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic in individuals with Noonan syndrome (ClinVar, DECIPHER, PMID: 31292302). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:5

Mar 15, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 17, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 30266093, 30417923, 26918529, 31219622, 31712860, 35390071, 34643321, 17143282, 17586837, 21387466, 26686981) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome

Pathogenic:3

May 25, 2012

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 10, 2019

ClinGen RASopathy Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1655G>A (p.Arg552Lys) variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837, 17143282, 30266093, 26686981). This variant has been detected in at least 7 independent occurrences with clinical features of a RASopathy (PS4; PMIDs: 17586837, 22420426, 28378436, 29037749, 25337068, 21387466, 21784453, 26918529, 21274610). In vitro functional studies provide some evidence that the p.Arg552Lys variant may impact protein function (PS3; PMID: 21784453). This residue has been defined as a PM1 hotspot by the RAS VCEP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg552Lys variant may impact the protein (PP3). 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 missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4, PS3, PM1_Strong, PM2, PP2, PP3. -

Sep 08, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg552Lys variant in SOS1 has been reported in at least six individuals with clinical features of Noonan syndrome, four of whom were reported to have occurr ed de novo (Tartaglia 2007, Zenker 2007, Lepri 2011). In addition this variant was absent from 600 control chromosomes (Lepri 2011). Furthermore, different ami no acid changes at this location (Arg552Gly, Arg552Thr and Arg552Ser) have also been associated with clinical features of Noonan syndrome (Roberts 2007, Zenker 2007, Tartaglia 2007, Beneteau 2009, Lepri 2011). Protein modeling suggests that amino acid residue 552 plays an important role in structural formation of the p rotein (Lepri 2011). Therefore, it is highly likely that this variant is pathog enic. The presence of a heterozygous pathogenic variant in SOS1 is consistent wi th a diagnosis of Noonan syndrome, but this information should be reconciled wit h the complete clinical history of this individual. -

Noonan syndrome 1

Pathogenic:2

Molecular Genetics, Centre for Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 3

Pathogenic:1

Feb 20, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The SOS1 c.1655G>A (p.Arg552Lys) variant lies in the helical linker between the PH and Rem domains and is predicted to interact directly with the side chains of Asp140 and Asp169 in the histone domain of SOS1 (ref. 16). Disruption of this interaction could affect the relative orientation of the DH-PH unit and the Rem domain (Tartaglia_207). This change involves the alteration of a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a deleterious outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), but multiple publications cite the variant as causative in affected individuals including at least one de novo event and a mother-child affected duo. In addition, Arg552 appears to be a mutational hot-spot as other alterations of the same codon, such as p.Arg552Gly and p.Arg552Ser were identified as causative in multiple NS pts and were shown to increase in the basal level of active RAS and prolonged RAS activation after EGF stimulation in functional studies (Tartaglia_ 2007). Lastly, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Fibromatosis, gingival, 1

Pathogenic:1

Apr 17, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as a de novo finding in patients with Noonan syndrome [PMID 17143282, 26686981] -

RASopathy

Pathogenic:1

Jan 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 552 of the SOS1 protein (p.Arg552Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 26686981, 30266093). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40683). Invitae Evidence 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 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. This variant disrupts the p.Arg552 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19020799, 21387466, 22190897, 24037001). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

D;D;T

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.9

D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.071

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.93

MutPred

0.81

Gain of ubiquitination at R552 (P = 0.0104);Gain of ubiquitination at R552 (P = 0.0104);Gain of ubiquitination at R552 (P = 0.0104);

MVP

0.88

MPC

1.5

ClinPred

0.94

GERP RS

5.8

Varity_R

0.83

gMVP

0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over