2-38986226-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1BP5
This summary comes from the ClinGen Evidence Repository: The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA297240/MONDO:0021060/004
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251300Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135802
GnomAD4 exome AF: 0.000252 AC: 368AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.000209 AC XY: 152AN XY: 727136
GnomAD4 genome AF: 0.000138 AC: 21AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74412
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2023 | SOS1: BS1 - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2024 | See Variant Classification Assertion Criteria. - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 21, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 09, 2024 | Variant summary: SOS1 c.3600C>G (p.Asp1200Glu) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251300 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome phenotype (3e-05). To our knowledge, no occurrence of c.3600C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 40733). Based on the evidence outlined above, the variant was classified as likely benign. - |
SOS1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 02, 2020 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2019 | 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. - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | - - |
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Jun 27, 2019 | The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at