rs397517159

Variant names:

• chr2-39007168-C-T
• rs397517159
• NM_005633.4:c.2536G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2 PP3 PM2 PM6 PM1 PS3

This summary comes from the ClinGen Evidence Repository: The c.2536G>A (p.Glu846Lys) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys variant may impact the protein (PP3). 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 missense variants are common (PP2; PMID:29493581). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PM6, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261734/MONDO:0018997/004

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 7.78
• Publications: 47 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• 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
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2536G>A	p.Glu846Lys	missense	Exon 16 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.2515G>A	p.Glu839Lys	missense	Exon 16 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.2536G>A	p.Glu846Lys	missense	Exon 16 of 22	NP_001369324.1	G5E9C8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2536G>A	p.Glu846Lys	missense	Exon 16 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.2536G>A	p.Glu846Lys	missense	Exon 16 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.2416G>A	p.Glu806Lys	missense	Exon 15 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
2	-	-	Noonan syndrome (2)
2	-	-	Noonan syndrome 4 (2)
2	-	-	RASopathy (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (1)
1	-	-	Noonan syndrome and Noonan-related syndrome (1)
1	-	-	SOS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.35	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.44
Sift	Benign	0.088	T
Sift4G	Benign	0.077	T
Polyphen		0.24	B
Vest4		0.87
MutPred		0.80		Gain of ubiquitination at E846 (P = 0.0162)
MVP		0.89
MPC		1.5
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.40
Mutation Taster		=8/92	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: rs397517159; hg19: chr2-39234309; COSMIC: COSV67673763;