2-39051211-G-C

Variant names:

• chr2-39051211-G-C
• rs137852812
• NM_005633.4:c.797C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_Moderate

The NM_005633.4(SOS1):​c.797C>G​(p.Thr266Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T266K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• fibromatosis, gingival, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary gingival fibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39051211-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12869.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP5: Variant 2-39051211-G-C is Pathogenic according to our data. Variant chr2-39051211-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1500284.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.797C>G	p.Thr266Arg	missense_variant	Exon 6 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.797C>G	p.Thr266Arg	missense_variant	Exon 6 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

RASopathy Pathogenic:1

Nov 24, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 266 of the SOS1 protein (p.Thr266Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. 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 disrupts the p.Thr266 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143285, 19020799, 19953625, 21387466). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.2	M;M;.
PhyloP100		9.9
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.43	B;B;.
Vest4		0.71
MutPred		0.55		Gain of catalytic residue at T266 (P = 0.022);Gain of catalytic residue at T266 (P = 0.022);Gain of catalytic residue at T266 (P = 0.022);
MVP		0.95
MPC		1.5
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.65
gMVP		0.91
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs137852812; hg19: chr2-39278352;