rs397517180

Positions:

• chr2-39035440-C-A
• chr2-39035440-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005633.4(SOS1):​c.925G>T​(p.Asp309Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D309N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.30

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39035440-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1333569.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 2-39035440-C-A is Pathogenic according to our data. Variant chr2-39035440-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 45379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39035440-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.925G>T	p.Asp309Tyr	missense_variant	7/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.925G>T	p.Asp309Tyr	missense_variant	7/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.925G>T;p.(Asp309Tyr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 45379; PMID: 17143285; 17586837; 18651097) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 17143285) - PS3_supporting. This variant is not present in population databases:rs397517180 , gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17143285; 17586837)PM6. The variant co-segregated with disease in multiple affected family members (PMID: 18651097) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an aspartic acid to a tyrosine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (DH-PH domain; PMID:17143285). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Variant identified in multiple individuals with Noonan syndrome (ClinVar, PMID: 17143285; 18651097). (P) 0903 - Low evidence for segregation with disease. Three individuals with Noonan syndrome over three generations (PMID: 18651097). (P) 1002 - Moderate functional evidence supporting abnormal protein function. This variant was shown to increase ERK activation compared to wild-type in transfected cells (PMID: 17143285). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2018

The D309Y variant has been published previously in association with Noonan syndrome, including an instance of de novo inheritance (Roberts et al., 2007; Zenker et al., 2007; Ezquieta et al., 2012). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. D309Y is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro studies have shown D309Y results in increased activation of ERK and RAS (Roberts et al., 2007). Additionally, the SOS1 gene has a low rate of benign missense variation and missense variants are a common mechanism of disease in this gene. Therefore, this variant is pathogenic. -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2017

The Asp309Tyr variant in SOS1 has been identified in at least 5 individuals with the clinical features of Noonan syndrome, occurred de novo in one of these indi viduals, and segregated with phenotypic features in 2 family members of one fami ly (Narumi 2008, Roberts 2007, Zenker 2007, LMM data). This variant has been ide ntified in large population studies. In addition, functional studies showed that this variant caused an increased EGF-evoked ERK activation, which is similar to PTPN11 disease-causing variants (Roberts 2007). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal domi nant manner based upon de novo occurrence, segregation studies, extremely low al lele frequency in the general population, and supporting functional evidence. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 21, 2021

This variant has been observed in individual(s) with Noonan syndrome (PMID: 17143285, 18651097, 17586837). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 45379). For these reasons, this variant has been classified as Pathogenic. 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 is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 309 of the SOS1 protein (p.Asp309Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Experimental studies have shown that this variant affects SOS1 protein function (PMID: 17143285). -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;D;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.2	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.89
MutPred		0.88		Loss of disorder (P = 0.0963);Loss of disorder (P = 0.0963);Loss of disorder (P = 0.0963);
MVP		0.89
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.63
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397517180; hg19: chr2-39262581; COSMIC: COSV67675939;