21-31659782-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000454.5(SOD1):c.13G>T(p.Ala5Ser) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.13G>T | p.Ala5Ser | missense_variant | 1/5 | ENST00000270142.11 | NP_000445.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.13G>T | p.Ala5Ser | missense_variant | 1/5 | 1 | NM_000454.5 | ENSP00000270142 | P1 | |
SOD1 | ENST00000389995.4 | c.13G>T | p.Ala5Ser | missense_variant, splice_region_variant | 1/5 | 3 | ENSP00000374645 | |||
SOD1 | ENST00000470944.1 | n.74G>T | non_coding_transcript_exon_variant | 1/5 | 2 | |||||
SOD1 | ENST00000476106.5 | n.90G>T | non_coding_transcript_exon_variant | 1/5 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 22, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala5 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7951249, 8179602, 8351519, 12792143, 17543992, 19176896, 19618436, 22292843). 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 variant affects SOD1 protein function (PMID: 21257910, 23280792, 26362407). 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. ClinVar contains an entry for this variant (Variation ID: 873321). This variant is also known as Ala4Ser. This variant has been observed in individuals with clinical features of SOD1-related conditions (PMID: 32579787; Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 5 of the SOD1 protein (p.Ala5Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. - |
Pathogenic, criteria provided, single submitter | research | Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University | Mar 31, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at