2-39023128-C-T

Position:

chr2-39023128-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM2PM5PP3_StrongPP5_Very_Strong

The NM_005633.4(SOS1):c.1300G>A(p.Gly434Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,202 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G434K) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.79

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:

SOS1 (HGNC:):

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PS1

Transcript NM_005633.4 (SOS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 2-39023128-C-T is Pathogenic according to our data. Variant chr2-39023128-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023128-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.1300G>A	p.Gly434Arg	missense_variant	10/23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.1300G>A	p.Gly434Arg	missense_variant	10/23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726894

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:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 4

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Apr 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 08, 2024	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) (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in two unrelated individuals with Noonan syndrome, once as de novo and once as maternally inherited (PMID: 30784236). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 05, 2019	The SOS1 c.1300G>A (p.Gly434Arg) variant is a missense variant that has been reported in at least two studies, in which it is found in a heterozygous state in three individuals with Noonan syndrome (Zenker et al. 2007; Lepri et al. 2011). Another variant that results in p.Gly434Arg has also been reported in at least three studies, in a total of five individuals with Noonan syndrome including a mother and son (Roberts et al. 2007; Alfieri et al. 2013; Koh et al. 2019). Phenotypes included cryptorchidism, pulmonary stenosis, short stature, mild hypertelorism, cubitus valgus, shield chest, and pectus deformity (Roberts et al. 2007; Koh et al. 2019). The p.Gly434Arg variant has been reported in a de novo state in at least two individuals (Zenker et al. 2007; Koh et al. 2019). Control data are unavailable for the p.Gly434Arg variant and it is not found in the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Gly434Arg variant is classified as pathogenic for Noonan syndrome. -

RASopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2018	Variant summary: SOS1 c.1300G>A (p.Gly434Arg) results in a non-conservative critical amino acid change located in the membrane-binding surface of the Pleckstrin Homology (PH) domain of the encoded protein sequence (Lepri_2011). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245568 control chromosomes (gnomAD). The variant, c.1300G>A, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Alfieri_2014, Binder_2012, Lepri_2011, Roberts_2007). These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, and demonstrated an increased capacity to induce ERK activation in starved cells (Smith_2013). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 09, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). 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. ClinVar contains an entry for this variant (Variation ID: 40672). This missense change has been observed in individuals with RASopathy spectrum disorders (PMID: 17143285, 17586837, 20186801, 21387466). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 434 of the SOS1 protein (p.Gly434Arg). -

Ptosis;C0349588:Short stature;C1860493:Abnormal sternum morphology;C1956257:Pulmonic stenosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Noonan syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn

- -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SOS1 NM_005633.3 exon 10 p.Gly434Arg (c.1300G>A): This variant has been reported in the literature in at least 3 individuals with a RASopathy, at least 1 of whom was identified to have this variant de novo (Zenker 2007 PMID:17586837, Lepri 2011 PMID:21387466). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:40672). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools for this variant are unclear. In vitro functional studies predict that this variant will impact the protein (Smith 2013 PMID:23487764). Of note, other variants that result in the same amino acid change as well as at this position have also been reported in the literature in association with disease (c.1300G>C Roberts 2007 PMID:17143285, p.Gly434Lys Lepri 2011 PMID:21387466) supporting the potential functional relevance of this codon. In summary, this variant is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 31, 2017

- -

Noonan syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 13, 2012

The 1300G>A (Gly434Arg) variant in SOS1 has previously been identified as a de n ovo variant in one individual with sporadic clinical features of Noonan syndrome (Zenker 2007). In addition, a different nucleotide change that causes the same amino acid change at this location (1300G>C) has also been associated with the c linical features of Noonan syndrome and was shown to have occurred de novo (Robe rts 2007). Therefore, this variant is highly likely to be pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2022

The p.G434R pathogenic mutation (also known as c.1300G>A), located in coding exon 10 of the SOS1 gene, results from a G to A substitution at nucleotide position 1300. The glycine at codon 434 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple Noonan syndrome cohorts; including a de novo occurrence (Roberts AE et al. Nat Genet, 2007 Jan;39:70-4; Zenker M et al. J Med Genet, 2007 Oct;44:651-6; Alfieri P et al. Am J Med Genet A, 2014 Apr;164A:934-42; Koh AL et al. Mol Genet Genomic Med, 2019 04;7:e00581; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337). In addition, this alteration may have an impact on protein function (Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Fetal cystic hygroma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

- -

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 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.6

M;M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-4.0

D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.029

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.85

Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);

MVP

0.98

MPC

1.0

ClinPred

0.97

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.66

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