14-50182521-A-T

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>A(p.Met267Lys) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M267R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• 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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain 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-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875
• PP5: Variant 14-50182521-A-T is Pathogenic according to our data. Variant chr14-50182521-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 209092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50182521-A-T is described in Lovd as [Pathogenic]. Variant chr14-50182521-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.800T>A	p.Met267Lys	missense_variant	6/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.800T>A	p.Met267Lys	missense_variant	6/22	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: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Pathogenic:6

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	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	clinical testing	Genome-Nilou Lab	-	- -
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, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -

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) -

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
MutationTaster	Benign	1.0	D;D
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;