14-50161551-G-C

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS1 PM2 PM5 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T376I) 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:9
• Conservation: PhyloP100: 9.60
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 9

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS1: Transcript NM_006939.4 (SOS2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50161551-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2821826.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 14-50161551-G-C is Pathogenic according to our data. Variant chr14-50161551-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 209091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	NM_006939.4	MANE Select	c.1127C>G	p.Thr376Ser	missense	Exon 9 of 23	NP_008870.2
	SOS2	NM_001411020.1		c.1028C>G	p.Thr343Ser	missense	Exon 8 of 22	NP_001397949.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.1127C>G	p.Thr376Ser	missense	Exon 9 of 23	ENSP00000216373.5
	SOS2	ENST00000543680.5	TSL:1	c.1028C>G	p.Thr343Ser	missense	Exon 8 of 22	ENSP00000445328.1
	SOS2	ENST00000555794.2	TSL:1	c.239C>G	p.Thr80Ser	missense	Exon 3 of 6	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

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.

Jun 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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).

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:3

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

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

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 v4.9

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
M_CAP	Benign	0.062	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.32	N
REVEL	Uncertain	0.37
Sift	Benign	0.74	T
Sift4G	Benign	0.18	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
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs869320687; hg19: chr14-50628269;