chr2-39054822-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_005633.4(SOS1):c.512T>G(p.Val171Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. V171A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_005633.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.512T>G | p.Val171Gly | missense_variant, splice_region_variant | 5/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.512T>G | p.Val171Gly | missense_variant, splice_region_variant | 5/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 17
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 26, 2017 | - - |
Noonan syndrome 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 03, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 25, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The Val171Gly v ariant in SOS1 has been previously identified in one individual with clinical fe atures of Noonan syndrome (LMM unpublished data). It was absent from large popul ation studies. In addition, another variant (Val171Ala) at the same codon was id entified as a de novo variant in one proband with clinical features of Noonan sy ndrome (LMM unpublished data) suggesting that changes at this position may not b e tolerated. Computational prediction tools and conservation analysis do not pro vide strong support for or against an impact to the protein. In summary, while t he available data on the Val171Gly variant is suspicious to be pathogenic, the c linical significance of this variant is uncertain. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 22, 2016 | This sequence change replaces valine with glycine at codon 171 of the SOS1 protein (p.Val171Gly). The valine residue is highly conserved and there is a moderate physicochemical difference between valine and glycine. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SOS1-related disease. ClinVar contains an entry for this variant (Variation ID: 40654). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at