rs121912458
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000454.5(SOD1):c.242A>G(p.His81Arg) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H81A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000454.5 missense, splice_region
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.242A>G | p.His81Arg | missense_variant, splice_region_variant | Exon 4 of 5 | ENST00000270142.11 | NP_000445.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251352Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135848
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:2
This sequence change replaces histidine with arginine at codon 81 of the SOD1 protein (p.His81Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 12402272). In at least one individual the variant was observed to be de novo. This variant is also known as His80Arg. ClinVar contains an entry for this variant (Variation ID: 14782). Experimental studies have shown that this variant affects SOD1 protein function (PMID: 16945901, 19483195, 20515040, 23280792). For these reasons, this variant has been classified as Pathogenic. -
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at