14-50182521-A-T

Position:

• chr14-50182521-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP3 PM2_Supporting PS2 PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.800T>A variant in SOS2 (NM_006939.4(SOS2):c.800T>A (p.Met267Lys)) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 267. It has been identified in at least 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV001426180.1, PMIDs: 25795793, 30707178). Two of these cases were reported as de novo occurrences, one with maternity and paternity confirmation and the other without (PS2, PM6; SCV001426180.1, PMID:25795793). The computational predictor REVEL gives a score of 0.802, which is above the threshold of 0.7, evidence that correlates with impact to SOS2 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied: PS2, PS4_Moderate, PM2_Supporting, PP3 (Version 2.1; 9/7/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA204984/MONDO:0021060/042

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel 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]

SOS2 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS2	NM_006939.4	c.800T>A	p.Met267Lys	missense_variant	6/23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.800T>A	p.Met267Lys	missense_variant	6/23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.800T>A	p.Met267Lys	missense_variant	6/22	1		ENSP00000445328.1
SOS2	ENST00000556469.5	n.567T>A		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Noonan syndrome 9 Pathogenic:6

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Human Genetics, University Hospital Magdeburg	Jul 02, 2020	This variant 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 variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6). The REVEL Score of this variant is 0.802 (PP3) and the variant has been classified as pathogenic in ClinVar (PP5). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2019	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: 26173643). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed to be de novo in an individual affected with Noonan syndrome (PMID: 25795793). ClinVar contains an entry for this variant (Variation ID: 209092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 267 of the SOS2 protein (p.Met267Lys). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and lysine. -
Pathogenic, criteria provided, single submitter	research	Genetics Laboratory, Instituto de Ciencias en Reproduccion Humana	Dec 30, 2019	This missense variant replaces methionine with lysine at codon 267 of the SOS2 protein (p.Met267Lys). This variant has been previously reported as pathogenic in a Brazilian patient with Noonan syndrome (PMID: 25795793). ACMG interpretation was pathogenic and the criteria used were: PS1 based on other aminoacids change M267R and M267T reported as pathogenic/likely pathogenic according ACMG criteria in Clinvar. PM1 because p.M267K is located in DH domain that is a well-established functional domain with other pathogenic variants. PM2 based on variant is not on gnomAD v2.1.1 and v3 and TOPMed Freeze 5. PP3 supporting disease causing by DEOGEN2, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. PP4 because the phenotype is highly suggestive a single disease, in this case a Rasopathy. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25795793, 27942422, 33750022, 30707178, 34006472, 35683512, 32788663, 26173643, 29696775) -

RASopathy Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Sep 17, 2024

The c.800T>A variant in SOS2 (NM_006939.4(SOS2):c.800T>A (p.Met267Lys)) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 267. It has been identified in at least 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV001426180.1, PMIDs: 25795793, 30707178). Two of these cases were reported as de novo occurrences, one with maternity and paternity confirmation and the other without (PS2, PM6; SCV001426180.1, PMID: 25795793). The computational predictor REVEL gives a score of 0.802, which is above the threshold of 0.7, evidence that correlates with impact to SOS2 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied: PS2, PS4_Moderate, PM2_Supporting, PP3 (Version 2.1; 9/7/2024) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.61	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.051	B;.
Vest4		0.96
MutPred		0.57		Gain of ubiquitination at M267 (P = 0.0075);Gain of ubiquitination at M267 (P = 0.0075);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs797045167; hg19: chr14-50649239; COSMIC: COSV53566628; COSMIC: COSV53566628;