rs201352584
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2
The NM_005633.4(SOS1):āc.233T>Gā(p.Phe78Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.233T>G | p.Phe78Cys | missense_variant | 3/23 | ENST00000402219.8 | NP_005624.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.233T>G | p.Phe78Cys | missense_variant | 3/23 | 1 | NM_005633.4 | ENSP00000384675.2 |
Frequencies
GnomAD3 genomes AF: 0.000171 AC: 26AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250656Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135582
GnomAD4 exome AF: 0.000124 AC: 181AN: 1460272Hom.: 0 Cov.: 29 AF XY: 0.000113 AC XY: 82AN XY: 726484
GnomAD4 genome AF: 0.000171 AC: 26AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | SOS1: PP3 - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 24, 2018 | This variant is associated with the following publications: (PMID: 24939586, 17586837, 21387466) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 30, 2017 | - - |
Noonan syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 01, 2021 | The c.233T>G (p.Phe78Cys) variant identified in the SOS1 gene substitues a Phenylalnine for Cysteine at amino acid 78/1334 (coding exon 2/23). It is identified in gnomAD (44 heterozygotes, 0 homozygotes; allele frequency 1.56e-4) and ExAC (15 heterozygotes, 0 homozygotes; allele frequency: 1.24e-4. In silico algorithms predict this variant will be Deleterious (Provean; Score: -7.01) and Damaging (SIFT;Score: 0.00) to the function of the canonical transcript. The c.233T>G (p.Phe78Cys) variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:40646), and has been described in two individuals in the literature who met clinical criteriafor Noonan syndrome [doi:10.4183/aeb.2014.463; PMID: 17586837], one of which was inherited from a presumably unaffected parent [PMID: 17586837]. Given the lack of compelling information supporting the pathogenicity of the c.233T>G (p.Phe78Cys) variant identified in this indivudal, it is reported here as a Variant of Uncertain Significance. - |
SOS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2023 | The SOS1 c.233T>G variant is predicted to result in the amino acid substitution p.Phe78Cys. This variant was reported in a patient with Noonan syndrome as well as their mother who was said to be clinically unaffected but was not available for phenotypic examination (Zenker et al. 2007. PubMed ID: 17586837). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-39285926-A-C), which is likely to high to be a primary cause of disease (Gelb et al. 2018. PubMed ID: 29493581). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Jan 31, 2019 | - - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 78 of the SOS1 protein (p.Phe78Cys). This variant is present in population databases (rs201352584, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with SOS1-related conditions (PMID: 17586837). ClinVar contains an entry for this variant (Variation ID: 40646). 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 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at