rs397517159
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PP2PP3PM2PM6PM1PS3
This summary comes from the ClinGen Evidence Repository: The c.2536G>A (p.Glu846Lys) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys variant may impact the protein (PP3). 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). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). 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): PP2, PP3, PM1, PM2, PM6, PS3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA261734/MONDO:0018997/004
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
Publications
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 4Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
- fibromatosis, gingival, 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- hereditary gingival fibromatosisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- cardiofaciocutaneous syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 12 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SOS1 | NM_005633.4 | c.2536G>A | p.Glu846Lys | missense_variant | Exon 16 of 23 | ENST00000402219.8 | NP_005624.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SOS1 | ENST00000402219.8 | c.2536G>A | p.Glu846Lys | missense_variant | Exon 16 of 23 | 1 | NM_005633.4 | ENSP00000384675.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 27
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:5
Published functional studies demonstrate that this variant results in increased EGF-evoked ERK activation and sustained endogenous RAS activation (Roberts et al., 2007); 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; This variant is associated with the following publications: (PMID: 26918529, 23673306, 24803665, 22555271, 21387466, 21041952, 18854871, 19077116, 17586837, 18651097, 17143282, 28492532, 30055033, 30417923, 31263281, 32753483, 33042901, 34184824, 30732632, 33219052, 17143285) -
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Noonan syndrome Pathogenic:2
The Glu846Lys variant in SOS1 has previously been identified in many individuals with clinical features of Noonan syndrome (Lepri 2011, Marco Tartaglia 2007, Ne umann 2009, Roberts 2007, Zenker 2007). This variant has shown segregation consi stent with pathogenicity in a familial case and to have occurred de novo in spor adic cases. In summary, this variant meets our criteria to be classified as path ogenic (http://pcpgm.partners.org/LMM). -
The c.2536G>A (p.Glu846Lys) variant in SOS1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 23673306). It has also been reported in a patient diagnosed with HCM (PMID 22555271). In vitro functional studies provide some evidence that the p.Glu846Lys variant may impact protein function (PS3; PMID 17143285). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Glu846Lys variant may impact the protein (PP3). 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). Furthermore, the variant is in a location that has been defined to be a mutational hotspot or domain of SOS1 (PM1; PMID 21387466). 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): PP2, PP3, PM1, PM2, PM6, PS3. -
RASopathy Pathogenic:2
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 846 of the SOS1 protein (p.Glu846Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17143282, 17143285, 17586837, 18651097, 18854871, 19077116, 21387466, 23673306). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40706). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. Experimental studies have shown that this missense change affects SOS1 function (PMID: 17143285, 21041952). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: SOS1 c.2536G>A (p.Glu846Lys) results in a conservative amino acid change located in the Ras guanine-nucleotide exchange factors catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 277182 control chromosomes (gnomAD and publication). The variant, c.2536G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome and Related Conditions (Zenker_2007, Tartaglia_2007, Lepri_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. Both heterozygous and homozygous mutant mice showed many NS-associated phenotypes, including growth delay, distinctive facial dysmorphia, hematologic abnormalities, and cardiac defects. Authors found that the Ras/MAPK pathway as well as Rac and Stat3 were activated in the mutant hearts (Chen_2010). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Noonan syndrome 4 Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 4 (MIM#610733) (PMID: 17143285). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301303). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated RasGEF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
SOS1-related disorder Pathogenic:1
The SOS1 c.2536G>A variant is predicted to result in the amino acid substitution p.Glu846Lys. This variant has previously been reported in individuals with Noonan syndrome and in at least one report to have arose de novo (see for example - Tartaglia et al 2007. PubMed ID: 17143282; Li et al. 2013. PubMed ID: 23673306; Hakami et al. 2016. PubMed ID: 26918529). Functional studies demonstrate this variant results in increased p-MEK/ERK levels, consistent with a gain-of-function mechanism, resulting in hyperactivation of the RAS pathway (Roberts et al. 2007. PubMed ID: 17143285). 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. -
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Pathogenic:1
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Cardiovascular phenotype Pathogenic:1
The p.E846K pathogenic mutation (also known as c.2536G>A), located in coding exon 16 of the SOS1 gene, results from a G to A substitution at nucleotide position 2536. The glutamic acid at codon 846 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple individuals with a clinical diagnosis of Noonan syndrome (Tartaglia M, Nat. Genet. 2007 Jan; 39(1):75-9; Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4; Zenker M, J. Med. Genet. 2007 Oct; 44(10):651-6; Neumann TE, Eur. J. Hum. Genet. 2009 Apr; 17(4):420-5; Lepri F, Hum. Mutat. 2011 Jul; 32(7):760-72; Li K, J Cutan Med Surg 2013 May-Jun; 17(3):212-8). In addition, functional studies demonstrated that this alteration resulted in increased RAS-ERK activation (Roberts AE, Nat. Genet. 2007 Jan; 39(1):70-4). Based on the supporting evidence, p.E846K is interpreted as a disease-causing mutation. -
Noonan syndrome and Noonan-related syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at