14-50161551-G-C

Variant names:

• chr14-50161551-G-C
• rs869320687
• NM_006939.4:c.1127C>G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_006939.4(SOS2):​c.1127C>G​(p.Thr376Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS2 NM_006939.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 9.60

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 12 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
• PP5: Variant 14-50161551-G-C is Pathogenic according to our data. Variant chr14-50161551-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 209091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50161551-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.1127C>G	p.Thr376Ser	missense_variant	Exon 9 of 23	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.1127C>G	p.Thr376Ser	missense_variant	Exon 9 of 23	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.1028C>G	p.Thr343Ser	missense_variant	Exon 8 of 22	1		ENSP00000445328.1
SOS2	ENST00000555794.2	c.239C>G	p.Thr80Ser	missense_variant	Exon 3 of 6	1		ENSP00000484766.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Pathogenic:4

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 proven to affect protein function using functional studies (PS3). It is absent from gnomAD (PM2). A variant at the analogous position in SOS1 (c.1132A>G) has been described as pathogenic (PM5). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6) and it has been classified as pathogenic in ClinVar (PP5). -

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant has been observed to segregate with Noonan syndrome in families (PMID:25795793, 26173643). ClinVar contains an entry for this variant (Variation ID: 209091). This variant has been reported to affect SOS2 protein function (PMID:26173643). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 376 of the SOS2 protein (p.Thr376Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. -

-

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Jun 20, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate increased RAS activation, supporting a gain of function (PMID: 26173643); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30707178, 27942422, 26446362, 29750912, 31573083, 34643321, 32788663, 26173643, 25795793, 27535533) -

Apr 27, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOS2: PS1, PM2, PS4:Moderate, PS2:Supporting, PS3:Supporting -

Noonan syndrome 1 Pathogenic:1

-

Molecular Genetics, Centre for Human Genetics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Noonan syndrome Pathogenic:1

Aug 03, 2015

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Benign	0.18	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.32	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.74	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;.
Vest4		0.72
MutPred		0.39		Gain of disorder (P = 0.0304);.;
MVP		0.91
MPC		0.55
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.16
gMVP		0.30

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: rs869320687; hg19: chr14-50628269;