rs727504636
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_005633.4(SOS1):c.3706C>A(p.Pro1236Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1236L) has been classified as Uncertain significance.
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.3706C>A | p.Pro1236Thr | missense_variant | 23/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.3706C>A | p.Pro1236Thr | missense_variant | 23/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152076Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251168Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135708
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461702Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727146
GnomAD4 genome ? AF: 0.000151 AC: 23AN: 152076Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74284
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 11, 2024 | Variant summary: SOS1 c.3706C>A (p.Pro1236Thr) 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 8e-06 in 251168 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.3706C>A 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: 179112). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 30, 2014 | p.Pro1236Thr in exon 23 of SOS1: This variant is not expected to have clinical s ignificance because it was identified in 2 probands with clinical features of No onan syndrome who inherited the variant from unaffected parents, one parent car ried the variant in an apparently homozygous state (LMM unpublished data). In ad dition, 2 unaffected siblings from one of these families also carried the varian t. This variant has also been identified in 1/67696 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). - |
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 01, 2022 | The SOS1 c.3706C>A (p.Pro1236Thr) missense change has a maximum subpopulation frequency of 0.0028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1236 of the SOS1 protein (p.Pro1236Thr). This variant is present in population databases (rs727504636, gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179112). 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 not expected to disrupt SOS1 protein function with a negative predictive value of 80%. 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. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 17, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 10, 2020 | 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