rs727504295

Positions:

• chr2-39023106-C-T

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.1322G>A​(p.Cys441Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,358 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 Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.79

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97
• PP5: Variant 2-39023106-C-T is Pathogenic according to our data. Variant chr2-39023106-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 40673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023106-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.1322G>A	p.Cys441Tyr	missense_variant	10/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.1322G>A	p.Cys441Tyr	missense_variant	10/23	1	NM_005633.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461358 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2023	Observed in many individuals in published literature with an SOS1-related disorder (Zenker et al., 2007; Pierpont et al., 2010; Lepri et al., 2011; Chinton et al., 2019; Shoji et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate normal to increased SOS1 activity (Gureasko et al., 2010, Smith et al., 2013); This variant is associated with the following publications: (PMID: 17143282, 24803665, 30417923, 31292302, 31560489, 19077116, 23487764, 17586837, 20186801, 12628188, 21387466, 29493581, 20648242, 34643321, 20133692) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 19, 2019	The SOS1 c.1322G>A; p.Cys441Tyr variant (rs727504295) is reported in the literature in multiple individuals affected with Noonan syndrome (Bessis 2019, Ko 2008, Lepri 2011, Pierpont 2010, Tartaglia 2007, Zenker 2007). In at least one affected individual, the variant was not observed in either parent, suggesting a de novo origin (Tartaglia 2007). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at amino acid 441 is highly conserved, and while functional studies indicate wildtype activation of pERK (Smith 2013), the variant also exhibits increased PIP2-dependent nucleotide exchange rates (Gureasko 2010). Additionally, other amino acid substitutions at nearby codons (p.Glu433Lys, p.Gly434Arg, p.Ile437Thr) have been reported in individuals with Noonan syndrome and are considered disease-causing (Lepri 2011, Tartaglia 2007, Zenker 2007), suggesting this region is functionally important. Based on available information, the p.Cys441Tyr variant is considered to be pathogenic. References: Bessis et al. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. Br J Dermatol. 2019 Jun;180(6):1438-1448. Gureasko J et al. Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3430-5. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Lepri F et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. Smith et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. Tartaglia et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. Zenker M et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007 Oct;44(10):651-6. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SOS1: PM6:Strong, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 09, 2024	Variant summary: SOS1 c.1322G>A (p.Cys441Tyr) results in a non-conservative amino acid change in 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 251002 control chromosomes. c.1322G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome including a de novo occurrence (e.g. Pierpont_2008, Ko_2008, Tartaglia_2007, Alfieri_2008, Lepri_2011, Lee_2011.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Gureasko_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19077116, 19020799, 17143282, 19568997, 20133692, 21387466, 21784453). ClinVar contains an entry for this variant (Variation ID: 40673). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 06, 2020	This sequence change replaces cysteine with tyrosine at codon 441 of the SOS1 protein (p.Cys441Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals affected with Noonan syndrome, including multiple de novo observations (PMID: 20186801, 21387466, 19077116, 17586837, 19020799 17143282, 17586837). ClinVar contains an entry for this variant (Variation ID: 40673). Experimental studies have shown that this missense change induces ERK activation similar to wild type, but increases SOS1 activity in a PIP2-dependent manner (PMID: 23487764, 20133692). For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

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Noonan syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2017

The p.Cys441Tyr variant in SOS1 has been previously identified in six individual s with clinical features of Noonan syndrome, including two confirmed de novo occ urrence (Tartaglia 2007, Zenker 2007, Lepri 2011, Korean Mutation Database, LMM data). This variant has not been identified in large population studies. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal do minant Noonan spectrum disorder based on presence in multiple affected individua ls including de novo occurrences. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-9.9	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.84		Loss of catalytic residue at M446 (P = 0.0424);Loss of catalytic residue at M446 (P = 0.0424);Loss of catalytic residue at M446 (P = 0.0424);
MVP		0.96
MPC		2.0
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.94

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: rs727504295; hg19: chr2-39250247; COSMIC: COSV67677222; COSMIC: COSV67677222;