rs142094234

Positions:

chr2-39051253-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1PP3_ModeratePP5BS2

The ENST00000402219.8(SOS1):c.755T>C(p.Ile252Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000354 in 1,611,604 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I252L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SOS1
ENST00000402219.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 9.20

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a helix (size 19) in uniprot entity SOS1_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in ENST00000402219.8

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

PP5

Variant 2-39051253-A-G is Pathogenic according to our data. Variant chr2-39051253-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496312.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5}. Variant chr2-39051253-A-G is described in Lovd as [Pathogenic]. Variant chr2-39051253-A-G is described in Lovd as [Likely_pathogenic].

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.755T>C	p.Ile252Thr	missense_variant	6/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.755T>C	p.Ile252Thr	missense_variant	6/23	1	NM_005633.4	ENSP00000384675	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000836

AC:

AN:

251312

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000356

AC:

AN:

1459302

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

726184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000446

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2017	Variant summary: The SOS1 c.755T>C (p.Ile252Thr) variant involves the alteration of a conserved nucleotide in the Dbl homology (DH) domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 9/121942 control chromosomes in ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.000259 (3/11562). This frequency is about 9 times the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003), suggesting this is possibly a benign polymorphism found primarily in the populations of Latino origin. This variant has been reported in multiple affected individuals with Noonan syndrome or Noonans related syndromes (Lepri_2011, Lepri_2014, Timeus_2013, and Moncini_2015). One reported family showed co-segregation of variant with disease, despite the clinical heterogeneous expressivity among the three affected individuals (Moncini_2015). Functional studies showed no or very mild activation of RAS-ERK pathway (Smith_2013 and Moncini_2015), which may explain the high MAF in population cohorts. Moncini_2015 detected differential allelic expression in all three patients from one family which may explain the clinical heterogeneous expressivity, and higher expression of the mutated allele in respect to the wild type possibly increasing the ERK activity. However, in another assay ERK activation was similar to wildtype (Smith_2013). An internal sample also carried a pathogenic variant in PTPN11 c.188A>G (p.Tyr63Cys), suggesting that the variant of interest was not the primary cause of the disease in the subject. Taken together, there is not enough evidence to prove the pathogenicity or neutrality of this variant; therefore it is currently classified as Variant of Unknown Significance until more evidence becomes available. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SOS1: PP1:Moderate, PS3:Moderate, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2024	Identified in patients with Noonan syndrome in published literature; this variant was also identified in other mildly affected family members (PMID: 25712082, 31368652); 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: 24451042, 30050098, 29907801, 21387466, 24803665, 23756559, 32065515, 34426522, 33446575, 29554876, 29493581, Toksoy2021[Case report], 23487764, 25712082, 36611340, 31847883, 34269737, 31368652, 37019085, Bianco2024[Article], 37217689) -

Noonan syndrome and Noonan-related syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

RASopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 252 of the SOS1 protein (p.Ile252Thr). This variant is present in population databases (rs142094234, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 21387466, 23756559, 25712082). ClinVar contains an entry for this variant (Variation ID: 496312). 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. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764, 25712082). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Noonan syndrome 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Mar 11, 2024

The SOS1 c.755T>C (p.Ile252Thr) missense change has a maximum subpopulation frequency of 0.026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PMID: 27535533) and the in silico tool REVEL predicts a deleterious effect on protein function. This variant has been reported in individuals with features suggestive of Noonan syndrome and/or individuals with mild Noonan syndrome phenotypes (PMID: 21387466, 22253195, 25712082, 31368652, 36611340, 37217689). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2021

The p.I252T variant (also known as c.755T>C), located in coding exon 6 of the SOS1 gene, results from a T to C substitution at nucleotide position 755. The isoleucine at codon 252 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals or cohorts reported to have Noonan syndrome (NS) or NS-related features, including an individual also with hypertrophic cardiomyopathy; however, clinical details were limited in some cases, some reported cases may overlap, and additional molecular findings were detected in at least one case (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Ferrero GB et al. Hum Mutat. 2012 Apr;33(4):703-9; Timeus F et al. Oncol Rep, 2013 Aug;30:553-9; Moncini S et al. Eur J Hum Genet, 2015 Nov;23:1531-7; Prasad A et al. BMC Med Genet, 2018 03;19:46Baban A et al. Am J Med Genet A, 2019 10;179:2083-2090; Leach NT et al. Genet Med, 2019 02;21:417-425). In one family, this variant segregated with variable NS features and carriers demonstrated differential allelic expression (Moncini S et al. Eur J Hum Genet, 2015 Nov;23:1531-7). In one functional study, this variant was reported to increase ERK phosphorylation; however, a second study did not detect increased ERK activation (Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9; Moncini S et al. Eur J Hum Genet, 2015 Nov;23:1531-7). This amino acid position is not well 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;D

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.7

M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.67

P;P;.

Vest4

0.94

MVP

0.99

MPC

1.5

ClinPred

0.49

GERP RS

5.7

Varity_R

0.70

gMVP

0.78

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