rs869320687

Positions:

• chr14-50161551-G-C

Variant summary

Our verdict is Pathogenic. Variant got 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 same amino acid change has been previously reported as Pathogenicin 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:8
• 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 16 ACMG points.

• PS1: Transcript NM_006939.4 (SOS2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 684625
• 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 id 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 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/exons	MANE	UniProt
SOS2	NM_006939.4	c.1127C>G	p.Thr376Ser	missense_variant	9/23	ENST00000216373.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS2	ENST00000216373.10	c.1127C>G	p.Thr376Ser	missense_variant	9/23	1	NM_006939.4	P1
SOS2	ENST00000543680.5	c.1028C>G	p.Thr343Ser	missense_variant	8/22	1
SOS2	ENST00000555794.2	c.242C>G	p.Thr81Ser	missense_variant	3/6	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2015	- -
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 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 18, 2019	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SOS2 protein function (PMID:26173643). 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 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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	Published functional studies demonstrate increased RAS activation, supporting a gain of function (Cordeddu et al., 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30707178, 27942422, 26446362, 29750912, 31573083, 27535533, 32788663, 26173643, 25795793) -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Molecular Genetics, Centre for Human Genetics

-

- -

Noonan syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

Aug 03, 2015

- -

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;.
MutationTaster	Benign	1.0	D;D
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;