rs121912447
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The ENST00000270142.11(SOD1):c.436G>A(p.Ala146Thr) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146D) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000270142.11 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.436G>A | p.Ala146Thr | missense_variant | 5/5 | ENST00000270142.11 | NP_000445.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.436G>A | p.Ala146Thr | missense_variant | 5/5 | 1 | NM_000454.5 | ENSP00000270142 | P1 | |
SOD1 | ENST00000389995.4 | c.379G>A | p.Ala127Thr | missense_variant | 5/5 | 3 | ENSP00000374645 | |||
SOD1 | ENST00000470944.1 | n.1364G>A | non_coding_transcript_exon_variant | 5/5 | 2 |
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, no assertion criteria provided | literature only | OMIM | Sep 01, 1995 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 07, 2022 | Experimental studies have shown that this missense change affects SOD1 function (PMID: 23280792). 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. 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: 14769). This variant is also known as p.Ala145Thr. This missense change has been observed in individuals with amyotrophic lateral sclerosis (ALS) (PMID: 7496169, 14506936, 22292843). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 146 of the SOD1 protein (p.Ala146Thr). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at