rs397517147

chr2-39023131-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_005633.4(SOS1):c.1297G>A(p.Glu433Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,082 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.79

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 14 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 2-39023131-C-T is Pathogenic according to our data. Variant chr2-39023131-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023131-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1297G>A	p.Glu433Lys	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1297G>A	p.Glu433Lys	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250760 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461082 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2023	Published functional studies demonstrate E433K increases the activation of RAS binding (Gureasko et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17586837, 21387466, 19020799, 18772396, 19953625, 17143282, 20133692, 20648242, 21851854, 21784453, 23756559, 24458522, 22848035, 18854871, 18456719, 24803665, 32036363, 31130284, 29493581, 12628188, 35792504, 34643321) -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 08, 2011

The Glu433Lys variant has been identified in the literature in several individua ls with clinical features of Noonan syndrome and one individual with Cardio-faci o-cutaneous syndrome (Ko 2008, Nystrom 2008, Tartaglia 2007, Denayer 2010). This variant has been reported to have occurred de novo in sporadic disease (Nystrom 2008, Denayer 2010). Therefore, it is highly likely that this variant is pathog enic. -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2023

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 sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 433 of the SOS1 protein (p.Glu433Lys). This variant is present in population databases (rs397517147, gnomAD 0.003%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 18456719, 19020799, 19953625). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40669). Experimental studies have shown that this missense change affects SOS1 function (PMID: 20133692). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.011	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.46	P;P;.
Vest4		0.98
MutPred		0.81		Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);Gain of MoRF binding (P = 0.0115);
MVP		0.99
MPC		0.76
ClinPred		0.81	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.74
gMVP		0.83

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

Other links and lift over

dbSNP: rs397517147; hg19: chr2-39250272; COSMIC: COSV67673993; COSMIC: COSV67673993;