chr2-39022779-A-G

Position:

• chr2-39022779-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_005633.4(SOS1):​c.1649T>C​(p.Leu550Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L550L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.20

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973
• PP5: Variant 2-39022779-A-G is Pathogenic according to our data. Variant chr2-39022779-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39022779-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1649T>C	p.Leu550Pro	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1649T>C	p.Leu550Pro	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461512 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727066

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SOS1: PS4, PM1, PM2, PM5, PP3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2018	The L550P variant has been previously published in association with Noonan syndrome (Tartaglia et al. 2007). The L550P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). L550P is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, in vitro studies have shown that L550P increases ERK activation and RAS exchange rates compared to wild type (Smith et al., 2013). Missense variants in nearby residues (S548R, T549K, R552W/G/T/K/M/S) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret L550P as a pathogenic variant. -

Noonan syndrome 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome (MIM#610733) (OMIM). Gain of function is established for the vast majority of missense variants however, loss of function has also been suggested for one missense variant due to the resulting unstable protein (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from leucine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. The variant is located in a cluster of pathogenic variants in the PH-REM linker domain (Decipher; PMID: 17143282). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 5 individuals with Noonan syndrome (ClinVar; PMIDs: 17143282, 18854871, 31560489, 31219622). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Mutant cDNA constructs transfected into HEK293T cells demonstrated increased pERK induction in serum starved cells and increased RAS exchange activity compared to wild type cDNA constructs (PMID: 23487764). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 08, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOS1 function (PMID: 23487764). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40680). This missense change has been observed in individuals with Noonan syndrome (PMID: 17143282, 18854871, 22190897, 24451042). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 550 of the SOS1 protein (p.Leu550Pro). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 20, 2020	Variant summary: SOS1 c.1649T>C (p.Leu550Pro) results in a non-conservative amino acid change located in the plekstrin homology domain-RAS exchanger motif domain linker (Tartaglia_2007) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251176 control chromosomes (gnomAD). c.1649T>C has been reported in the literature in multiple individuals affected with Noonan Syndrome (Tartaglia_2007, Neumann_2008, Digilio_2011, Lepri_2014, Li_2019), including cosegregating with disease in families (Tartaglia_2007). These data indicate that the variant is very likely to be associated with disease. In vitro studies report this variant results in increased ERK activation and RAS exchange rate compared to wild type in cells. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Noonan syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

research

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

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SOS1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 01, 2023

The SOS1 c.1649T>C variant is predicted to result in the amino acid substitution p.Leu550Pro. This variant has been reported in an individual with Noonan Syndrome (Tartaglia et al. 2007. PubMed ID: 17143282; Chinton et al. 2019. PubMed ID: 31560489; Table S1 - Li et al. 2019. PubMed ID: 31219622). Functional studies demonstrated elevated levels of pERK and an increased rate of RAS nucleotide exchange, consistent with a gain-of-function mechanism (Smith et al. 2013. PubMed ID: 23487764). Additionally, different amino acid substitutions near this residue (p.Ser548Arg, p.Thr549Lys, p.Arg552Gly, p.Arg552Trp, p.Arg552Lys, p.Arg552Thr, p.Arg552Met, p.Arg552Ser) have been reported as pathogenic (Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been interpreted as pathogenic by multiple clinical labs in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/40680/). This variant is interpreted as pathogenic. -

Noonan syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 04, 2006

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Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

The p.L550P variant (also known as c.1649T>C), located in coding exon 10 of the SOS1 gene, results from a T to C substitution at nucleotide position 1649. The leucine at codon 550 is replaced by proline, an amino acid with similar properties. This alteration has been reported in individuals with Noonan syndrome (Tartaglia M et al. Nat Genet, 2007 Jan;39:75-9; Chinton J et al. Arch Argent Pediatr, 2019 Oct;117:330-337; Li X et al. Clin Genet, 2019 Oct;96:290-299; Follansbee CW et al. HeartRhythm Case Rep, 2021 Aug;7:510-513; Papadopoulos G et al. Eur J Pediatr, 2022 Oct;181:3691-3700). In an assay testing SOS1 function, this variant showed a functionally abnormal result (Smith MJ et al. Proc Natl Acad Sci U S A, 2013 Mar;110:4574-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.5	D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.82		Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);Gain of disorder (P = 0.0245);
MVP		0.97
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.93

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: rs397517153; hg19: chr2-39249920;