chr2-39056862-A-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. BS2PP3BP5
This summary comes from the ClinGen Evidence Repository: The c.350T>G (p.Val117Gly) variant has been identified in a patient with clinical features of a RASopathy with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; GeneDx, Partners LMM; GTR ID's: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). Computational prediction tools and conservation analysis suggest that the p.Val117Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, BS2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136140/MONDO:0021060/004
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.350T>G | p.Val117Gly | missense_variant | 4/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.350T>G | p.Val117Gly | missense_variant | 4/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250366Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135600
GnomAD4 exome AF: 0.0000131 AC: 19AN: 1449516Hom.: 0 Cov.: 27 AF XY: 0.0000152 AC XY: 11AN XY: 722092
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 24, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Val117Gly varia nt in SOS1 has been identified in 1 stillborn fetus and 1 Ashkenazi Jewish indiv idual with Noonan syndrome who also carried a pathogenic variant in PTPN11. In addition, the variant was also identified in the unaffected mothers of both of t hese individuals (LMM unpublished data, pers. com. Cedars-Sinai). This variant h as also been identified in 0.1% (1/943) of European chromosomes by the ClinSeq p roject (dbSNP rs201085754). Computational prediction tools and conservation anal ysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the Val117Gly variant is uncertain, its presence in 3 apparently healthy individuals suggest that it is more likely to be benign. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 14, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2023 | Variant summary: SOS1 c.350T>G (p.Val117Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 250366 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.350T>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. The available evidence is currently insufficient to determine the role of this variant in disease. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
RASopathy Benign:2
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.350T>G (p.Val117Gly) variant has been identified in a patient with clinical features of a RASopathy with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM GTR Lab ID: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). This variant was observed in a healthy adult individual who did not have clinical features of a RASopathy (BS2; GeneDx, Partners LMM; GTR ID's: 26957, 21766; ClinVar SCV000062230.5, SCV000209093.5). Computational prediction tools and conservation analysis suggest that the p.Val117Gly variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP5, BS2, PP3. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jun 17, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2022 | The p.V117G variant (also known as c.350T>G), located in coding exon 4 of the SOS1 gene, results from a T to G substitution at nucleotide position 350. The valine at codon 117 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at