21-31659779-A-G
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000454.5(SOD1):c.10A>G(p.Lys4Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000454.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.10A>G | p.Lys4Glu | missense_variant | Exon 1 of 5 | 1 | NM_000454.5 | ENSP00000270142.7 | ||
SOD1 | ENST00000389995.4 | c.10A>G | p.Lys4Glu | missense_variant | Exon 1 of 5 | 3 | ENSP00000374645.4 | |||
SOD1 | ENST00000470944.1 | n.71A>G | non_coding_transcript_exon_variant | Exon 1 of 5 | 2 | |||||
SOD1 | ENST00000476106.5 | n.87A>G | non_coding_transcript_exon_variant | Exon 1 of 5 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461554Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 727116
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:1
This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4 of the SOD1 protein (p.Lys4Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18852346, 23898858, 32729725). This variant is also known as K3E. ClinVar contains an entry for this variant (Variation ID: 2138372). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SOD1 function (PMID: 23280792). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect on conformation of SOD1 proteins (Fujisawa et al., 2012); Also known as p.K3E; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23280792, 18852346, 34996976, 32729725, 23898858) -
SOD1-related disorder Pathogenic:1
The SOD1 c.10A>G variant is predicted to result in the amino acid substitution p.Lys4Glu. This variant has been reported in multiple unrelated individuals with amyotrophic lateral sclerosis (Takahashi et al. 2008. PubMed ID: 18852346; Kuźma-Kozakiewicz et al. 2013. PubMed ID: 23898858; Shibuya et al. 2020. PubMed ID: 32729725; Berdyński et al. 2022. PubMed ID: 34996976). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at