NM_005633.4:c.512T>G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS4_ModeratePS2PM2PP2PP3
This summary comes from the ClinGen Evidence Repository: The c.512T>G (p.Val171Gly) variant has been identified in a patient with clinical features of a RASopathy in a de novo occurance (PS2; Ambry Genetics internal data, GTR ID: 61756, ClinVar SCV000742607.1) This variant has also been identified in two other independent occurrences in patients with clinical features of a RASopathy (PS4_Moderate PMID:26918529, Partners LMM, Invitae internal data; GTR ID: 21766, 500031 ClinVar SCV000062241.5, SCV000553263.2). Of note, a different likely pathogenic missense variant (p.Val171Ala) has been previously identified at this codon of SOS1 (PM5 not met; ClinVar 45373). The p.Val171Gly variant in the SOS1 gene was absent from gnomAD (PM2). Computational prediction tools and conservation analysis suggest that the p.Val171Gly variant may impact the protein (PP3). Of note, the variant occurs at the second nucleotide of exon 5 (in-frame) but no functional evidence has indicated that the variant would cause skipping of the exon. The variant is located in the SOS1 gene, 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, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Moderate, PM2, PP3, PP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA136165/MONDO:0018997/004
Frequency
Consequence
NM_005633.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 17
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Inborn genetic diseases Pathogenic:1
- -
Noonan syndrome 4 Pathogenic:1
- -
RASopathy Pathogenic:1
This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 171 of the SOS1 protein (p.Val171Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 26918529, 35253369; internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Val171 amino acid residue in SOS1. Other variant(s) that disrupt this residue have been observed in individuals with SOS1-related conditions (PMID: 29402968), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
not specified Uncertain:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at