rs80265967
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2
The NM_000454(SOD1):c.272A>C(p.Asp91Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 152172 control chromosomes in the gnomAD Genomes database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting interpretations of pathogenicity (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91V) has been classified as Pathogenic.
Frequency
Consequence
NM_000454 missense
Scores
Clinical Significance
Conservation
Links
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOD1 | NM_000454.5 | c.272A>C | p.Asp91Ala | missense_variant | 4/5 | ENST00000270142.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOD1 | ENST00000270142.11 | c.272A>C | p.Asp91Ala | missense_variant | 4/5 | 1 | NM_000454.5 | P1 | |
ENST00000609934.1 | upstream_gene_variant |
Frequencies
GnomAD3 genomes AF: 0.00119 AC: 181AN: 152172Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00143 AC: 360AN: 251472Hom.: 2 AF XY: 0.00134 AC XY: 182AN XY: 135916
GnomAD4 exome AF: 0.000928 AC: 1357AN: 1461822Hom.: 3 AF XY: 0.000914 AC XY: 665AN XY: 727214
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:6Uncertain:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 10, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Mar 30, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Cologne University | Apr 25, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.150%). The variant is observed as homozygous in at least two unrelated individuals/adults in the gnomAD v.2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SOD1 related disorder (ClinVar ID: VCV000014766 / PMID: 7647793). Different missense changes at the same codon (p.Asp91Asn, p.Asp91Val) have been reported to be associated with SOD1 related disorder (PMID: 22632444). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 13, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 12, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | research | Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University | Mar 31, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 91 of the SOD1 protein (p.Asp91Ala). This variant is present in population databases (rs80265967, gnomAD 1.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive amyotrophic lateral sclerosis (PMID: 7647793, 10809943, 11220750, 11284995, 11369193, 14506936, 18608106, 19703565, 20460594, 22264771, 23062701, 23280792). This variant has been reported in individual(s) with autosomal dominant amyotrophic lateral sclerosis (PMID: 8909456, 10809943, 14506936, 19922148, 22264771); however, the role of the variant in this condition is currently unclear. This variant is also known as p.Asp90Ala. ClinVar contains an entry for this variant (Variation ID: 14766). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SOD1 function (PMID: 7655469, 12482932, 16945901, 17420412, 18319614, 19635794, 19703565, 20189984, 22264771, 25509359, 25792239). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Pathogenic:3Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 14, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 29, 2016 | The D91A variant in the SOD1 gene has been reported multiple times, using alternate nomenclature (D90A), in association with familial ALS. When found in the homozygous and compound heterozygous state D91A has been reported as a disease-associated variant (Hand et al., 2001; Andersen et al., 1995; Felbecker et al., 2010). However, in the heterozygous state the pathogenicity of the the D91A variant is debated (Al-Chalabi et al., 1998; Felbecker et al., 2010). The D91A variant is found with significant frequency among Scandinavian populations (Al-Chalabi et al., 1998); and the NHLBI ESP Exome Sequencing Project reports D91A was observed at a frequency of 0.08%, 7/8600 alleles, from individuals of European ancestry, indicating it may be a rare variant in this population. The D91A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved across species. Functional studies suggest that the D91A variant may not alter protein activity and stability to the same degree as other established SOD1 variants associated with familial ALS (Själander et al., 1995; Fujisawa et al., 2012; Lindberg et al., 2002). Given the available information, we interpret D91A as a variant of unknown significance. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics Inc | Jun 22, 2020 | This is a founder variant with reported recessive and dominant disease inheritance (PMID 12442272), and so its frequency in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant is also referred to as p.Asp90Ala in published literature. This variant associates with disease in multiple families reported to exhibit both autosomal dominant and autosomal recessive inheritance. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments show this variant causes increased protein aggregation causing motor neuron degeneration (PMID 17146286, 18319614, 19483195, 25806427). - |
Amyotrophic lateral sclerosis 1, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 10, 2007 | - - |
Amyotrophic lateral sclerosis Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust | Jan 01, 2022 | - - |
Amyotrophic Lateral Sclerosis, Dominant Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
Source:
Splicing
Find out SpliceAI and Pangolin per-transcript scores at