rs121912439
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000454.5(SOD1):c.302A>G(p.Glu101Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000454.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.302A>G | p.Glu101Gly | missense_variant | 4/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.302A>G | p.Glu101Gly | missense_variant | 4/5 | 1 | NM_000454.5 | P1 | |
SOD1 | ENST00000389995.4 | c.245A>G | p.Glu82Gly | missense_variant | 4/5 | 3 | |||
SOD1 | ENST00000470944.1 | n.1230A>G | non_coding_transcript_exon_variant | 4/5 | 2 | ||||
SOD1 | ENST00000476106.5 | n.565A>G | non_coding_transcript_exon_variant | 5/5 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 24, 1995 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 101 of the SOD1 protein (p.Glu101Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant SOD1-related conditions (PMID: 28105640). ClinVar contains an entry for this variant (Variation ID: 14761). 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. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 20399791, 23280792, 26362407). This variant disrupts the p.Glu101 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875253, 15258228, 20540686, 22292843). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Motor neuron disease Pathogenic:1
Pathogenic, criteria provided, single submitter | case-control | Centre for Genomic and Experimental Medicine, University of Edinburgh | Aug 31, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2023 | Published functional studies demonstrate that the variant increases aggregation of the SOD1 protein and decreases protein stability (Prudencio et al., 2009; Vassall et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7635196, 23280792, 20399791, 18951903, 21257910, 26362407, 8891072, 32006803, 28105640, 28089114, 32789025, 7624031, 8446170, 19483195) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at