2-39023134-A-G

Position:

• chr2-39023134-A-G

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000402219.8(SOS1):​c.1294T>C​(p.Trp432Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W432C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 ENST00000402219.8 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.19

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 26 ACMG points.

• PS1: Transcript ENST00000402219.8 (SOS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1712183
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000402219.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39023132-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2725108.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 2-39023134-A-G is Pathogenic according to our data. Variant chr2-39023134-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023134-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1294T>C	p.Trp432Arg	missense_variant	10/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1294T>C	p.Trp432Arg	missense_variant	10/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 4 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Sep 30, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2009	- -
Pathogenic, no assertion criteria provided	research	Department of Genetics, Beijing BioBiggen Technology Co., Ltd.	Jun 29, 2022	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 17, 2023	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 432 of the SOS1 protein (p.Trp432Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 17586837, 19438935, 21387466, 22465605). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12873). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2020	Variant summary: SOS1 c.1294T>C (p.Trp432Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251056 control chromosomes. c.1294T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome And Related Conditions, including some de novo cases (Tartaglia_2007, Zenker_2007, Hanna_2009, Ezquieta_2012, Jin_2017). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2014

The W432R missense mutation in the SOS1 gene has been reported in association with Noonan syndrome (Tartaglia et al., 2007). W432R is a non-conservative amino acid substitution that occurs within the highly conserved pleckstrin homology (PH) domain. Furthermore, the W432R 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. The variant is found in NOONAN panel(s). -

Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 18, 2013

The Trp432Arg variant has been reported in the literature in several individuals with clinical features of Noonan syndrome (Hanna 2009, Lepri 2011, Tartaglia 20 07, Zenker 2007, LMM unpublished data). This variant showed segregation in one f amily with clinical features of Noonan syndrome and multiple giant cell lesions consistent with pathogenicity (2 meioses; Hanna 2009). This variant is highly li kely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;D;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-13	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.86		Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.97
gMVP		0.94

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: rs267607080; hg19: chr2-39250275; COSMIC: COSV67674426; COSMIC: COSV67674426;