chr14-50182521-A-C

Variant names:

• chr14-50182521-A-C
• NM_006939.4:c.800T>G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_006939.4(SOS2):​c.800T>G​(p.Met267Arg) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M267K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.32

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain DH (size 190) in uniprot entity SOS2_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_006939.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50182521-A-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 14-50182521-A-C is Pathogenic according to our data. Variant chr14-50182521-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 577079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.800T>G	p.Met267Arg	missense_variant	Exon 6 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.800T>G	p.Met267Arg	missense_variant	Exon 6 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.800T>G	p.Met267Arg	missense_variant	Exon 6 of 22	1		ENSP00000445328.1
SOS2	ENST00000556469.5	n.567T>G		non_coding_transcript_exon_variant	Exon 5 of 5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Pathogenic:4

Mar 23, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PM5,PP3. -

-

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 SOS2 protein function. ClinVar contains an entry for this variant (Variation ID: 577079). This missense change has been observed in individuals with Noonan syndrome (PMID: 26173643; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 267 of the SOS2 protein (p.Met267Arg). Experimental studies have shown that this missense change affects SOS2 function (PMID: 26173643). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met267 amino acid residue in SOS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25795793). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

Jul 02, 2020

Department of Human Genetics, University Hospital Magdeburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as pathogenic including well-established functional studies (PS1 and PS3). It is absent from gnomAD (PM2). Variants at the analogous position in SOS1 (c.806T>G and c.806T>C) have been classified as pathogenic (PM5_Strong). The REVEL score of this variant is 0.919 (PP3) and the variant has been classified as likely pathogenic in ClinVar (PP5). -

SOS2-related disorder Pathogenic:1

Nov 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOS2 c.800T>G variant is predicted to result in the amino acid substitution p.Met267Arg. This variant as been reported in multiple individuals with Noonan syndrome, being documented as occurring de novo in at least one individual (Cordeddu et al. 2015. PubMed ID: 26173643; Lissewski et al. 2020. PubMed ID: 32788663). This variant has not been reported in a large population database, indicating this variant is rare. Alternative substitutions (Lys, Thr) at this amino acid position have also been reported as causative for Noonan syndrome (Yamamoto et al. 2015. PubMed ID: 25795793; Lissewski et al. 2021. PubMed ID: 32788663). This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Oct 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate variant promotes enhanced phosphorylation of extracellular signal-regulated kinase (ERK) compared to wild type protein (Cordeddu et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30707178, 26173643, 27942422, 29696775, 30417923, 32788663) -

Noonan syndrome Pathogenic:1

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

RASopathy Pathogenic:1

Jun 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SOS2 c.800T>G (p.Met267Arg) results in a non-conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of 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 251306 control chromosomes (gnomAD). c.800T>G has been reported in the literature in multiple individuals affected with Noonan Syndrome (Cordeddu_2015, Bessis_2019, Lissewski_2021, Lallar_2021). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant increases RAS and MEK/ERK activation (Cordeddu_2015). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.87	P;.
Vest4		0.97
MutPred		0.67		Loss of glycosylation at T268 (P = 0.0641);Loss of glycosylation at T268 (P = 0.0641);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50649239; COSMIC: COSV53564283; COSMIC: COSV53564283;