2-39054822-A-G

Position:

• chr2-39054822-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM6 PS4_Supporting PP2 PM5

This summary comes from the ClinGen Evidence Repository: The c.512T>C (p.Val171Ala) variant in SOS1 has been reported as an unconfirmed de novo occurrence in a patient with clinical features of a Noonan spectrum disorder (PM6; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062240.5). The p.Val171Ala variant has also been identified in another independent occurrences in patients with clinical features of a familial RASopathy (PS4_Supporting; PMID:29402968). This variant was absent from large population studies (PM2; gnomAD, http://gnomAD.broadinstitute.org). A different pathogenic missense variant (p.Val171Gly) has been previously identified at this codon of SOS1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40654). 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PS4_Supporting, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261743/MONDO:0021060/004

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense, splice_region
• Scores: Splicing: ADA: 0.9503
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 8.64

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.512T>C	p.Val171Ala	missense_variant, splice_region_variant	5/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.512T>C	p.Val171Ala	missense_variant, splice_region_variant	5/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.49e-7 AC: 1 AN: 1177672 Hom.: 0 Cov.: 17 AF XY: 0.00000167 AC XY: 1 AN XY: 599598

Gnomad4 AFR exome AF: 0.00

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: 0.00000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Aug 31, 2020

- -

Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 25, 2014

The Val171Ala variant in SOS1 has been previously identified in one individual w ith clinical features of a Noonan spectrum disorder and was identified to occur de novo (LMM unpublished data). It was absent from large population studies. Com putational prediction tools and conservation analysis do not provide strong supp ort for or against an impact to the protein. In summary, while the available dat a on the Val171Ala variant is suspicious to be pathogenic, the clinical signific ance of this variant is uncertain. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Feb 28, 2019

The c.512T>C (p.Val171Ala) variant in SOS1 has been reported as an unconfirmed de novo occurrence in a patient with clinical features of a Noonan spectrum disorder (PM6; Partners LMM internal data; GTR Lab ID: 21766; ClinVar SCV000062240.5). The p.Val171Ala variant has also been identified in another independent occurrences in patients with clinical features of a familial RASopathy (PS4_Supporting; PMID: 29402968). This variant was absent from large population studies (PM2; gnomAD, http://gnomAD.broadinstitute.org). A different pathogenic missense variant (p.Val171Gly) has been previously identified at this codon of SOS1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 40654). 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). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PM5, PM2, PS4_Supporting, PP2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;D;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	.;T;D
M_CAP	Uncertain	0.088	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.57
Sift	Benign	0.19	T;T;T
Sift4G	Uncertain	0.044	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.89
MutPred		0.35		Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);
MVP		0.93
MPC		1.7
ClinPred		0.98	D
GERP RS		6.1
Varity_R		0.37
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.48
SpliceAI score (max)		0.010		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: rs397517174; hg19: chr2-39281963;