chr2-39054822-A-C

Variant names:

• chr2-39054822-A-C
• rs397517174
• NM_005633.4:c.512T>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:3 U:1
• 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 rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.512T>G	p.Val171Gly	missense_variant, splice_region_variant	Exon 5 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.512T>G	p.Val171Gly	missense_variant, splice_region_variant	Exon 5 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 26, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Noonan syndrome 4 Pathogenic:1

Nov 03, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 171 of the SOS1 protein (p.Val171Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 26918529, 35253369; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Val171 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been observed in individuals with SOS1-related conditions (PMID: 29402968), which suggests that this may be a clinically significant amino acid residue. 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. -

not specified Uncertain:1

Sep 25, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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;.
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;