rs367693130
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
This summary comes from the ClinGen Evidence Repository: The c.3721A>G (p.Lys1241Glu) variant in SOS1 was present in 0.0017% (1/113488 CI 95%) of European alleles in gnomADv2.1.1 (BS1 not met; PMID:29493581). It has been identified in healthy individuals without clinical features of a RASopathy, but this information does not meet the current criteria to apply BS2 (Ambry Genetics internal data). The variant is located in SOS1, 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). In summary, the clinical significance of the p.Lys1241Glu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136152/MONDO:0021060/004
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251104Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461686Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 727140
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74184
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2009 | - - |
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2020 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in relation to a Noonan-spectrum disorder to our knowledge; This variant is associated with the following publications: (PMID: 27418595) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2024 | The p.K1241E variant (also known as c.3721A>G), located in coding exon 23 of the SOS1 gene, results from an A to G substitution at nucleotide position 3721. The lysine at codon 1241 is replaced by glutamic acid, an amino acid with similar properties. This alteration was reported in an individual with tetralogy of Fallot (LaHaye S et al. Circ Cardiovasc Genet, 2016 Aug;9:320-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 19, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at