2-39024080-T-C

Variant names:

• chr2-39024080-T-C
• rs397517146
• NM_005633.4:c.1132A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_005633.4(SOS1):​c.1132A>G​(p.Thr378Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T378T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.57
• Publications: 8 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-39024080-T-C is Pathogenic according to our data. Variant chr2-39024080-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3614934). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1132A>G	p.Thr378Ala	missense_variant	Exon 9 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1132A>G	p.Thr378Ala	missense_variant	Exon 9 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Alfa AF: 0.000151 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 4 Pathogenic:2

Jan 31, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.86 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000045344). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Nov 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 34411415, 21387466, 32627323, 36959127, 30712878) -

Noonan syndrome Pathogenic:1

Oct 04, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr378Ala variant in SOS1 has been previously reported in the literature in one individual with clinical features of an unspecified Noonan spectrum disorder (cohort consisted of individuals with Noonan syndrome, CFC syndrome, or nonsynd romic congenital heart defects) and was absent in 600 control chromosomes (Lepri 2011). This variant has also been observed in one individual by our laboratory and was found to have occurred de novo. Computational analyses (biochemical amin o acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that th e Thr378Ala variant may not impact the protein, though this information is not p redictive enough to rule out pathogenicity. In summary, additional information i s needed to fully assess the clinical significance of the Thr378Ala variant. -

Cardiovascular phenotype Pathogenic:1

Jul 01, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T378A pathogenic mutation (also known as c.1132A>G), located in coding exon 9 of the SOS1 gene, results from an A to G substitution at nucleotide position 1132. The threonine at codon 378 is replaced by alanine, an amino acid with similar properties. This variant has been detected in multiple individuals with a clinical diagnosis or suspicion of Noonan syndrome; it has also been determined to be the result of a de novo mutation or germline mosaicism in multiple families (Denayer E et al. Genes Chromosomes Cancer, 2010 Mar;49:242-52; Ambry internal data; personal communication with other laboratories). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

RASopathy Pathogenic:1

Jun 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 45344). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 19953625; Invitae; ClinVar). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 378 of the SOS1 protein (p.Thr378Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;T;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.4	M;M;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.12	N;N;N
REVEL	Benign	0.25
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.070	T;T;T
Polyphen		0.15	B;B;.
Vest4		0.55
MutPred		0.46		Loss of methylation at K374 (P = 0.0671);Loss of methylation at K374 (P = 0.0671);Loss of methylation at K374 (P = 0.0671);
MVP		0.77
MPC		0.81
ClinPred		0.56	D
GERP RS		5.9
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.4
Varity_R		0.46
gMVP		0.51
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs397517146; hg19: chr2-39251221;