2-39022773-C-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3PP2PS4_ModeratePM1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID:21387466). his AA residue has been specified as a hotspot for variation. 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Met 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16616762/MONDO:0021060/004

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:5

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PS4

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

PM1

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>T	p.Arg552Met	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>T	p.Arg552Met	missense_variant	Exon 10 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250906

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135598

show subpopulations

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Mar 23, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM1_Strong, PP2, PP3 -

Jul 21, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 30417923, 31219622, 20648242, 29493581, 17143282, 21387466, 12628188) -

Noonan syndrome

Pathogenic:1

Aug 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg552Met variant in SOS1 has been reported in the literature in two patients with clinical features of Noonan Syndrome (Lepri 2011). Furthermore, several other amino acid changes at this position have been reported in association with Noonan syndrome (Arg552Ser, Arg552Lys, Arg552Thr, Arg552Gly; Beneteau 2009, Lepri 2011, LMM unreported data). This variant was also shown to be absent from 600 control chromosomes and has not been identified in large and broad populations by the NHLBI Exome Sequencing Project (Lepri 2011, http://evs.gs.washington.edu/EVS/). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Arg552Met variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

May 10, 2019

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1655G>T (p.Arg552Met) variant has been identified in at least 3 independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate; GeneDx internal data; GTR Lab IDs 26957; SCV000565586.5 PMID: 21387466). his AA residue has been specified as a hotspot for variation. 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Met 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 likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1_Strong, PP2, PP3. -

RASopathy

Pathogenic:1

Aug 06, 2024

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 methionine, which is neutral and non-polar, at codon 552 of the SOS1 protein (p.Arg552Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 21387466, 30417923, 31219622; Invitae). ClinVar contains an entry for this variant (Variation ID: 40681). 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 95%. 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: 17143282, 17586837, 18854871, 21340158, 21387466, 23487764, 25073238). 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

0.99

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Benign

0.96

DEOGEN2

Pathogenic

0.94

D;D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-5.8

D;D;D

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.88

MutPred

0.54

Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);Loss of solvent accessibility (P = 0.0058);

MVP

0.97

MPC

1.6

ClinPred

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.84

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