2-39022782-G-T

Variant names:

• chr2-39022782-G-T
• rs730881046
• NM_005633.4:c.1646C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PM2

This summary comes from the ClinGen Evidence Repository: The c.1646C>A (p.Thr549Lys) variant in SOS1 was absent from large population studies (PM2; gnomad.broadinstitute.org). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID:29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PM2, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA297273/MONDO:0021060/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 9.86
• Publications: 3 publications found

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]

SOS1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• fibromatosis, gingival, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary gingival fibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005633.4. 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
	SOS1	NM_005633.4	MANE Select	c.1646C>A	p.Thr549Lys	missense	Exon 10 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.1625C>A	p.Thr542Lys	missense	Exon 10 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.1646C>A	p.Thr549Lys	missense	Exon 10 of 22	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.1646C>A	p.Thr549Lys	missense	Exon 10 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.1646C>A	p.Thr549Lys	missense	Exon 10 of 22	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.1535C>A	p.Thr512Lys	missense	Exon 9 of 22	ENSP00000508626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Apr 08, 2014

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr549Lys (ACA>AAA): c.1646 C>A in exon 10 of the SOS1 gene (NM_005633.3). The T549K missense change in the SOS1 gene has been reported as a possibly pathogenic variant (Lepri et al., 2011). The T549K variant 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 well conserved across species and is within the helical linker domain, which connects the pleckstrin homology (PH) domain and Ras exchanger motif (REM) (Lepri et al., 2011). Missense mutations in nearby residues (S548R, L550P, R552G, R552K, R552M, R552S, R552T, R552W) within the same domain have been reported in association with Noonan syndrome, supporting the functional importance of this region of the protein. Furthermore, the T549K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in NOONAN panel(s).

RASopathy Pathogenic:1

May 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 549 of the SOS1 protein (p.Thr549Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This missense change is located in a region of the SOS1 protein where a significant number of previously reported SOS1 missense mutations are found (PMID: 21387466). These observations suggest that this may be a clinically significant region of the protein. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 21387466, 29907801, Invitae). ClinVar contains an entry for this variant (Variation ID: 181553).

not specified Uncertain:1

Feb 28, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SOS1 c.1646C>A (p.Thr549Lys) results in a non-conservative amino acid change in the encoded protein sequence. The variant is located at a helical linker (residues 548-558) that was suggested to be functionally important to maintain the structural stability of the protein (Lepri_2011 and PMID: 20133692), and variants in this linker, such as S548R, L550P, R552G/K/S/T, have been classified as disease variants by our laboratory and/or other clinical labs, indicating the functional importance of this protein region. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.1646C>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Leach_2019, Lepri_2011). Specifically, the variant was identified in 1 internal prenatal sample referred for genetic testing with clinical indication of cystic hygroma and edema (Leach_2019) and it was confirmed to be de novo following parental testing. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Cardiovascular phenotype Uncertain:1

Jan 31, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T549K variant (also known as c.1646C>A), located in coding exon 10 of the SOS1 gene, results from a C to A substitution at nucleotide position 1646. The threonine at codon 549 is replaced by lysine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with Noonan syndrome (Leach NT et al. Genet Med, 2019 Feb;21:417-425; Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.45		Gain of ubiquitination at T549 (P = 0.0138)
MVP		0.97
MPC		0.84
ClinPred		0.75	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.77
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: rs730881046; hg19: chr2-39249923;