rs267607079

chr2-39022772-C-Achr2-39022772-C-G

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005633.4(SOS1):c.1656G>T(p.Arg552Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,482 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 Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R552G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 0.623

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 Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript NM_005633.4 (SOS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 12872
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39022774-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12871.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 2-39022772-C-A is Pathogenic according to our data. Variant chr2-39022772-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 40684.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39022772-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1656G>T	p.Arg552Ser	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1656G>T	p.Arg552Ser	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461482 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727056

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 18, 2018	The SOS1: c.1656G>T; p.Arg552Ser variant has been previously reported in association with Noonan syndrome (Zenker 2007, Neumann 2009) and is listed in ClinVar as pathogenic (Variation ID: 40684). Numerous variants of the arginine at codon 552 including p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, and p.Arg552Trp have all been associated with Noonan syndrome suggesting this amino acid is important for SOS1 protein function (Tartaglia 2007, Zenker 2007, Neumann 2009). Functional studies performed on the p.Arg552Gly variant indicate that it causes persistent ERK and RAS signaling activity upon ligand stimulation consistent with the established molecular mechanisms of the disease. (Tartaglia 2007). This variant is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on these observations the c.1656G>T; p.Arg552Ser variant has been classified pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Different missense variants involving this residue (p.R552W, p.R552K, p.R552T, p.R552G, p.R552M) or neighboring residues (p.T549K , p.T549KA, p.L550P, p.D555E, p.V556I) have been reported in individuals with Noonan spectrum disorders in ClinVar, HGMD, and/or individuals tested at GeneDx; Missense variants in this gene are often considered pathogenic (HGMD); 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: 18651097, 22848035, 22488759, 28378436, 18854871, 17586837, 20648242, 29493581, 17143282, 21387466, 12628188, 30417923, 31219622, 31785789) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

RASopathy Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 30, 2017	Variant summary: The SOS1 c.1656G>T (p.Arg552Ser) variant involves the alteration of a non conserved nucleotide. The variant is located within the helical linker between the PH and Rem domains (Sondermann_2005) and 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from control dataset of gnomAD (~245640 chrs tested), but was identified in several NS pts as a de novo event (Zenker_2007; Neumann_2009; Narumi_2008) and was shown to segregate in at least one familial case (Zenker_2007). Another alteration of the same nucleotide, c.1656G>C, leading to the identical alteration on the protein level, p.Arg552Ser, has been reported in multiple NS pts and is classified as Pathogenic. The codon Arg552 appears to be a mutational hot-spot, as other alteration, such as R552G, R552T, R552K, R552M have been reported in patients with NS. Taken together, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2023	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 552 of the SOS1 protein (p.Arg552Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome and cardio-facio-cutaneous (CFC) syndrome (PMID: 17586837, 18651097, 18854871). ClinVar contains an entry for this variant (Variation ID: 40684). 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. 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, 17143285, 17586837, 19352411, 20493809, 21387466, 23487764). 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. -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040684). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 17586837, 18854871) and reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 18854871). In addition, It has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 17586837). Different missense changes at the same codon (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Thr, p.Arg552Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012871, VCV000040681, VCV000040682, VCV000040683, VCV000372656). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

-

ACMG categories: PS2,PM1,PM2,PP3,PP5 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2008

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2016

The p.R552S pathogenic mutation (also known as c.1656G>T), located in coding exon 10 of the SOS1 gene, results from a G to T substitution at nucleotide position 1656. The arginine at codon 552 is replaced by serine, an amino acid with dissimilar properties. This mutation has been reported in sporadic and familial cases of Noonan syndrome (Zenker M, J. Med. Genet. 2007 Oct; 44(10):651-6; Neumann TE, Eur. J. Hum. Genet. 2009 Apr; 17(4):420-5) and a different nucleotide substitution (c.1656G>C), resulting in the same amino acid change, was confirmed de novo in affected individuals in another study (Tartaglia M, Nat. Genet. 2007 Jan; 39(1):75-9). In addition, substitutions of the R552 residue have been reported to account for one-third of SOS1 mutations in Noonan syndrome, with multiple mutations having been reported at this codon, including: p.552G, p.552K, p.552M, p.552T, and p.552W (Lepri F, Hum. Mutat. 2011 Jul; 32(7):760-72; Ezquieta B, Rev Esp Cardiol (Engl Ed) 2012 May; 65(5):447-55). Based on the supporting evidence, p.R552S is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

May 10, 2019

The c.1656G>T (p.Arg552Ser) variant in SOS1 has been reported as a confirmed de novo occurrence in one patient and 2 other probands with clinical features of a RASopathy (PS2, PS4_Moderate; PMID 17586837, 18854871). Of note, one of these cases was an affected mother-child duo (PP1 not met; PMID: 17586837). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). This amino acid residue has been designated as a hotspot. 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). Of note, the p.Arg552Ser variant in SOS1 has also been a consequence of the c.1656G>C nucleotide change which has been classified as pathogenic (PS1; ClinVar ID 12872). Computational prediction tools and conservation analysis suggest that the p.Arg552Ser 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, PS1, PM1_Strong, PM2, PS4_Moderate, PP2, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.70	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.6	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.85		Loss of MoRF binding (P = 0.0526);Loss of MoRF binding (P = 0.0526);Loss of MoRF binding (P = 0.0526);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.95
gMVP		0.87

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: rs267607079; hg19: chr2-39249913;