14-50161551-G-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1PM2PM5PP5_Very_Strong
The NM_006939.4(SOS2):c.1127C>G(p.Thr376Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T376I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_006939.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS2 | NM_006939.4 | c.1127C>G | p.Thr376Ser | missense_variant | 9/23 | ENST00000216373.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS2 | ENST00000216373.10 | c.1127C>G | p.Thr376Ser | missense_variant | 9/23 | 1 | NM_006939.4 | P1 | |
SOS2 | ENST00000543680.5 | c.1028C>G | p.Thr343Ser | missense_variant | 8/22 | 1 | |||
SOS2 | ENST00000555794.2 | c.242C>G | p.Thr81Ser | missense_variant | 3/6 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Noonan syndrome 9 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, University Hospital Magdeburg | Jul 02, 2020 | This variant has been proven to affect protein function using functional studies (PS3). It is absent from gnomAD (PM2). A variant at the analogous position in SOS1 (c.1132A>G) has been described as pathogenic (PM5). The variant is assumed to be de novo, but without confirmation of paternity and maternity (PM6) and it has been classified as pathogenic in ClinVar (PP5). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 18, 2019 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SOS2 protein function (PMID:26173643). This missense variant has been observed to segregate with Noonan syndrome in families (PMID:25795793, 26173643). ClinVar contains an entry for this variant (Variation ID: 209091). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with serine at codon 376 of the SOS2 protein (p.Thr376Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Apr 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 02, 2022 | Published functional studies demonstrate increased RAS activation, supporting a gain of function (Cordeddu et al., 2015); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30707178, 27942422, 26446362, 29750912, 31573083, 27535533, 32788663, 26173643, 25795793) - |
Noonan syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics, Centre for Human Genetics | - | - - |
Noonan syndrome Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Aug 03, 2015 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at