2-39022773-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PM6PP2PP3PS4_ModeratePM1_Strong
This summary comes from the ClinGen Evidence Repository: The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID:21387466, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The p.Arg552 residue has been defined as a hotspot by the RAS EP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Thr variant may impact the protein (PP3). 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): PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261728/MONDO:0018997/004
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Noonan syndrome 4 Pathogenic:3
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The SOS1 c.1655G>C missense variant is classified as PATHOGENIC (PM1, PP3, PS2, PS4) (PM2 and PP2 not applied due to using PS4 and PM1) The SOS1 c.1655G>C missense variant is a single nucleotide change in exon 10 of the SOS1 gene, which is predicted to change the amino acid arginine at position 552 in the protein to threonine. The variant is de novo (both maternity and paternity confirmed) in a patient with the disease and no family history (PS2). The variant has been reported in multiple patients with Noonan syndrome (PMID:19352411, PMID:21387466) (PS4). The variant is in dbSNP (rs397517154) but is absent from population databases. The variant has been reported in ClinVar as pathogenic for Noonan syndrome, by multiple submitters, including the ClinGen RASopathy variant classification expert panel (Variation ID: VCV000040682.6), and has also been reported in HGMD as damaging for Noonan syndrome (CM095735) and LOVD as pathogenic (SOS1_00020). This is a missense variant in a constrained gene where missense variants are a common mechanism of disease and benign variation is rare. The amino acid arginine at position 552 is located within a mutational hot spot and is frequently altered in Noonan syndrome patients with SOS1 variants (PM1). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (PMID:29493581). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000040682). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 19352411, 21387466). Different missense changes at the same codon (p.Arg552Gly, p.Arg552Lys, p.Arg552Met, p.Arg552Ser, p.Arg552Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012871, VCV000012872, VCV000040681, VCV000040683, VCV000040684, VCV000372656). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Noonan syndrome Pathogenic:3
The c.1655G>C (p.Arg552Thr) variant in SOS1 has been identified in at least 4 independent occurrences in patients with clinical features of a RASopathy, one of which was de novo (PS4_Moderate; GeneDx, St. George's Hospital, London internal data; GTR Lab ID: 26957 SCV000209121.12; PMID: 21387466, 19352411). This variant was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). The p.Arg552 residue has been defined as a hotspot by the RAS EP. These variants would have received PM5_Strong but the RAS EP decided that PM1 and PM5 cannot be used simultaneously and therefore this rule has been upgraded with expert judgement (PM1_Strong). 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). Computational prediction tools and conservation analysis suggest that the p.Arg552Thr variant may impact the protein (PP3). 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): PS4_Moderate, PM1_Strong, PM2, PM6, PP2, PP3. -
The p.Arg552Thr variant in SOS1 has been identified in at least 5 individuals wi th clinical features of Noonan syndrome (Beneteau 2009, Lepri 2011, LMM unpublis hed data) and was absent from large population studies. Arginine (Arg) at positi on 552 is highly conserved in mammals, and evolutionarily distant species and ot her computational prediction tools suggest that this variant may impact the prot ein. Furthermore, several other amino acid changes at this position have been id entified in individuals with Noonan syndrome (p.Arg552Ser, p.Arg552Lys, p.Arg552 Met, p.Arg552Gly; Beneteau 2009, Lepri 2011), many of which occurred de novo, an d functional studies showed that another variant at the same position (p.Arg552G ly) caused increased and prolonged RAS activation (Tartaglia 2007). In summary, this variant meets our criteria to be classified as pathogenic for Noonan syndro me in an autosomal dominant manner based upon absence from controls and supporti ng functional evidence. -
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not provided Pathogenic:2
Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21387466, 24803665, 19352411, 36140671, 12628188, 17143282, 20648242, 29493581, 33128510, 35386434, Bolat2022[CaseReport], 26607044) -
The SOS1 c.1655G>C (p.Arg552Thr) missense variant results in the substitution of arginine at amino acid position 552 with threonine. Across a selection of the available literature, the p.Arg552Thr variant has been reported in a heterozygous state in at least five unrelated individuals with Noonan syndrome, including at least one confirmed de novo occurrence (PMID: 19352411; PMID: 21387466; PMID: 26607044; PMID: 33128510; https://doi.org/10.3390/genes13091503). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Arg552 is well-characterized mutational hotspot within the SOS1 protein, with missense variants at this residue accounting for approximately one third of SOS1-related Noonan syndrome cases (PMID: 21387466; PMID: 29493581). Based on the available evidence, c.1655G>C (p.Arg552Thr) variant is classified as pathogenic for Noonan syndrome. -
Noonan syndrome 1 Pathogenic:1
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Abnormal aortic valve morphology Pathogenic:1
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SOS1-related disorder Pathogenic:1
The SOS1 c.1655G>C variant is predicted to result in the amino acid substitution p.Arg552Thr. This variant has been reported in multiple individuals with Noonan syndrome (Beneteau et al. 2009. PubMed ID: 19352411; Lepri et al. 2011. PubMed ID: 21387466). Alternate missense variants affecting this residue (p.Arg552Gly, p.Arg552Trp, p.Arg552Lys, p.Arg552Met, p.Arg552Ser) have been interpreted as pathogenic (ClinVar IDs: 12871, 372656, 40683, 40681, 12872, 40684). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -
Cardiovascular phenotype Pathogenic:1
The p.R552T pathogenic mutation (also known as c.1655G>C), located in coding exon 10 of the SOS1 gene, results from a G to C substitution at nucleotide position 1655. The arginine at codon 552 is replaced by threonine, an amino acid with similar properties. This variant has been reported in multiple individuals with Noonan syndrome (Beneteau C et al. Eur J Hum Genet, 2009 Oct;17:1216-21; Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; izmárová M et al. Ann Hum Genet, 2016 Jan;80:50-62; Bertola DR et al. Am J Med Genet C Semin Med Genet, 2020 12;184:896-911). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Gureasko J et al. Proc Natl Acad Sci U S A, 2010 Feb;107:3430-5). Multiple alterations at the same codon, including p.R552G (c.1654A>G), p.R552K (c.1655G>A), and p.R552S (c.1656G>C, c.1656G>T), have been detected in Noonan syndrome cohorts (Tartaglia M et al. Nat Genet, 2007 Jan;39:75-9; Zenker M et al. J Med Genet, 2007 Oct;44:651-6). 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
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RASopathy Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 552 of the SOS1 protein (p.Arg552Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 19352411, 21387466; LaboratoryofMolecularMedicineClinVarentry, internal data). ClinVar contains an entry for this variant (Variation ID: 40682). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SOS1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg552 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17143282, 23487764). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at