rs397517174

Positions:

• chr2-39054822-A-C
• chr2-39054822-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP2 PP3 PS4_Moderate PS2

This summary comes from the ClinGen Evidence Repository: The c.512T>G (p.Val171Gly) variant has been identified in a patient with clinical features of a RASopathy in a de novo occurance (PS2; Ambry Genetics internal data, GTR ID: 61756, ClinVar SCV000742607.1) This variant has also been identified in two other independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate PMID:26918529, Partners LMM, Invitae internal data; GTR ID: 21766, 500031 ClinVar SCV000062241.5, SCV000553263.2). Of note, a different likely pathogenic missense variant (p.Val171Ala) has been previously identified at this codon of SOS1 (PM5 not met; ClinVar 45373). The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2). Computational prediction tools and conservation analysis suggest that the p.Val171Gly variant may impact the protein (PP3). Of note, the variant occurs at the second nucleotide of exon 5 (in-frame) but no functional evidence has indicated that the variant would cause skipping of the exon. 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, PS4_Moderate, PM2, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136165/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Scores: Splicing: ADA: 0.9503
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 8.64

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 10 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.512T>G	p.Val171Gly	missense_variant, splice_region_variant	5/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.512T>G	p.Val171Gly	missense_variant, splice_region_variant	5/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2017

- -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Nov 03, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2014

Variant classified as Uncertain Significance - Favor Pathogenic. The Val171Gly v ariant in SOS1 has been previously identified in one individual with clinical fe atures of Noonan syndrome (LMM unpublished data). It was absent from large popul ation studies. In addition, another variant (Val171Ala) at the same codon was id entified as a de novo variant in one proband with clinical features of Noonan sy ndrome (LMM unpublished data) suggesting that changes at this position may not b e tolerated. Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, while t he available data on the Val171Gly variant is suspicious to be pathogenic, the c linical significance of this variant is uncertain. -

RASopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2016

This sequence change replaces valine with glycine at codon 171 of the SOS1 protein (p.Val171Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 40654). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.5	D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.39		Loss of stability (P = 0.0052);Loss of stability (P = 0.0052);Loss of stability (P = 0.0052);
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.75
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.020		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: rs397517174; hg19: chr2-39281963; COSMIC: COSV67677736; COSMIC: COSV67677736;