2-39023118-A-G

Position:

• chr2-39023118-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_005633.4(SOS1):​c.1310T>C​(p.Ile437Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,344 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.19

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896
• PP5: Variant 2-39023118-A-G is Pathogenic according to our data. Variant chr2-39023118-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 45345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-39023118-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1310T>C	p.Ile437Thr	missense_variant	10/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1310T>C	p.Ile437Thr	missense_variant	10/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461344 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726964

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Apr 20, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 30541462, 30039904, 24451042, 21387466, 33042901, 20648242, 29493581, 17143282, 12628188, 31785789) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Noonan syndrome 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.I437T in SOS1 (NM_005633.4) has been reported previously in individuals affected with Noonan syndrome, including an apparently de novo occurrence (Lepri et al., 2011; Lepri et al., 2014). Missense variants in the same residue (I437N) and in nearby residues (W432R, E433K, G434R, C441Y) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The p.I437T variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between isoleucine and threonine. The p.I437T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The isoleucine residue at codon 437 of SOS1 is conserved in all mammalian species. The nucleotide c.1310 in SOS1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Noonan syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 12, 2014	The p.Ile437Thr variant in SOS1 has been reported in two individuals with clinic al features of Noonan syndrome and was determined to have occurred de novo in on e of them (Lepri 2011). In addition, this variant has been identified by our lab oratory in >5 individuals with clinical features of Noonan syndrome and segregat ed with disease in 4 affected relatives from 2 families (LMM data). This variant was absent from large population studies. In summary, this variant meets criter ia to be classified as pathogenic for Noonan syndrome in an autosomal dominant m anner. -

RASopathy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2023	Variant summary: SOS1 c.1310T>C (p.Ile437Thr) results in a non-conservative amino acid change located in the plekstrin homology domain of 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 250826 control chromosomes.The variant was absent in 245614 control chromosomes (gnomAD). The variant, c.1310T>C, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions, and in at least one case was reported as a de novo mutation (Lepri_2011, Prasad_2018). Additionally, a different variant at the same codon has been classified as pathogenic/likely pathogenic in ClinVar (p.Ile437Ser). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21387466, 22585553, 30039904). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 437 of the SOS1 protein (p.Ile437Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 21387466, 24451042). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 45345). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Male subfertility Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Dec 01, 2023

The main focus of the current study was analyzing men with spermatogenic failure. This case belonged to the control group but was later found to have subfertility. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

SOS1 NM_005633.3 exon 10 p.Ile437Thr (c.1310T>C): This variant has been reported in the literature in multiple individuals with Noonan syndrome, including two cases reported to be de novo (Lepri 2011 PMID:21387466, Prasad 2018 PMID:30039904, Yang 2018 PMID:30541462). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:45345). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2021

The p.I437T pathogenic mutation (also known as c.1310T>C), located in coding exon 10 of the SOS1 gene, results from a T to C substitution at nucleotide position 1310. The isoleucine at codon 437 is replaced by threonine, an amino acid with similar properties, and is located in the pleckstrin homology domain. This mutation has been detected in several unrelated individuals reported to have Noonan syndrome, including de novo occurrences in affected index cases (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Moniez S et al. Eur J Endocrinol, 2018 Dec;179:409-418; Prasad RM et al. Pediatr Blood Cancer, 2018 11;65:e27362; Yang L et al. BMC Med Genet, 2018 12;19:212; Ferriero K et al. Front Pediatr, 2020 Sep;8:515; Lazzaro G et al. Mol Genet Genomic Med, 2020 04;8:e1069). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Noonan syndrome and Noonan-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.82	P;P;.
Vest4		0.98
MutPred		0.65		Gain of disorder (P = 0.0387);Gain of disorder (P = 0.0387);Gain of disorder (P = 0.0387);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.79
gMVP		0.87

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: rs397517150; hg19: chr2-39250259;