21-31659788-T-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000454.5(SOD1):c.19T>G(p.Cys7Gly) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C7W) has been classified as Pathogenic.
Frequency
Consequence
NM_000454.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.19T>G | p.Cys7Gly | missense_variant | Exon 1 of 5 | 1 | NM_000454.5 | ENSP00000270142.7 | ||
SOD1 | ENST00000389995.4 | c.15+4T>G | splice_region_variant, intron_variant | Intron 1 of 4 | 3 | ENSP00000374645.4 | ||||
SOD1 | ENST00000470944.1 | n.80T>G | non_coding_transcript_exon_variant | Exon 1 of 5 | 2 | |||||
SOD1 | ENST00000476106.5 | n.96T>G | non_coding_transcript_exon_variant | Exon 1 of 5 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250532Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135708
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:1
This variant disrupts the p.Cys7 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21073275, 21329474, 21603025). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOD1 function (PMID: 23280792). 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 expected to disrupt SOD1 protein function. This variant is also known as p.Cys6Gly. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 10624810). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 7 of the SOD1 protein (p.Cys7Gly). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at