2-39023128-C-G

Position:

• chr2-39023128-C-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005633.4(SOS1):​c.1300G>C​(p.Gly434Arg) 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 Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G434K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• 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]

SOS1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_005633.4 (SOS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 2-39023128-C-G is Pathogenic according to our data. Variant chr2-39023128-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 40670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023128-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1300G>C	p.Gly434Arg	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.1300G>C	p.Gly434Arg	missense_variant	10/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 29, 2019

The SOS1 c.1300G>C; p.Gly434Arg variant has been described in individuals with Noonan syndrome (NS; Koh 2019, Roberts 2007). It is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. Functional analyses of the p.Gly434Arg variant demonstrate increased activation over wildtype, consistent with other NS-causing variants (Smith 2013). Additionally, another variant that results in the same amino acid change at this codon (c.1300G>A; p.Gly434Arg) has been described in at least one individual affected with NS (Zenker 2007). Based on available information, the c.1300G>C variant is considered pathogenic. REFERENCES Koh A et al. The spectrum of genetic variants and phenotypic features of Southeast Asian patients with Noonan syndrome. Mol Genet Genomic Med. 2019 Apr; 7(4): e00581. Roberts A et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007 Jan;39(1):70-4. Smith M et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. Zenker M et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007 Oct;44(10):651-6. -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 05, 2019

PS2, PS3, PS4_moderate, PM1, PM2, PP3 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2024

The p.G434R pathogenic mutation (also known as c.1300G>C), located in coding exon 10 of the SOS1 gene, results from a G to C substitution at nucleotide position 1300. The glycine at codon 434 is replaced by arginine, an amino acid with dissimilar properties. This variant was reported in multiple individuals with features consistent with Noonan syndrome, including a de novo occurrence (Roberts AE et al. Nat Genet, 2007 Jan;39:70-4; Pierpont EI et al. Am J Med Genet A, 2010 Mar;152A:591-600; Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Koh AL et al. Mol Genet Genomic Med, 2019 Apr;7:e00581). A different alteration located at the same position, resulting in the same protein change, c.1300G>A (p.G434R), has been detected in individuals with Noonan syndrome (Zenker M et al. J Med Genet, 2007 Oct;44:651-6; Alfieri P et al. Am J Med Genet A, 2014 Apr;164A:934-42; Chinton J et al. Arch Argent Pediatr, 2019 10;117:330-337). In an assay testing SOS1 function, this variant showed a functionally abnormal result (Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Fibromatosis, gingival, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 23, 2021

- -

RASopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 21, 2020

This variant has been reported to have conflicting or insufficient data to determine the effect on SOS1 protein function (PMID: 23487764). For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individuals and families affected with clinical features of Noonan syndrome, in at least one of whom it was found de novo (PMID: 17143285, 20186801, 17586837, 21387466, 30784236). This sequence change replaces glycine with arginine at codon 434 of the SOS1 protein (p.Gly434Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.95
MutPred		0.85		Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);Gain of MoRF binding (P = 0.0401);
MVP		0.98
MPC		1.0
ClinPred		0.96	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.66
gMVP		0.84

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: rs397517148; hg19: chr2-39250269;