rs142094234

chr2-39051253-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PP3_Moderate PP5 BS2

The NM_005633.4(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 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4
• Conservation: PhyloP100: 9.20

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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a helix (size 19) in uniprot entity SOS1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_005633.4
• 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: {Uncertain_significance=4, Likely_pathogenic=2}. 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 GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.755T>C	p.Ile252Thr	missense_variant	6/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.755T>C	p.Ile252Thr	missense_variant	6/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152184 Hom.: 0 Cov.: 32

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: 21 AN: 251312 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135838

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: 52 AN: 1459302 Hom.: 0 Cov.: 29 AF XY: 0.0000454 AC XY: 33 AN XY: 726184

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: 5 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74482

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.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

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	Mar 03, 2023	Identified in a patient with Noonan syndrome in published literature; this variant was also identified in other members of the proband's family who were mildly affected and in one unaffected individual in the control population (Moncini et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24451042, 31368652, 30050098, 29907801, 21387466, 24803665, 25712082, 23756559, 32065515, 34426522, 33446575, 29554876, 29493581, Toksoy2021[Case report], 31847883, 36611340, 34269737, 23487764) -
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. -

RASopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

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 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

- -

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	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Pathogenic	27
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	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
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	T
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

Other links and lift over

dbSNP: rs142094234; hg19: chr2-39278394;