rs80265967
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1PM5BP4_ModerateBS2
The NM_000454.5(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 0.000953 in 1,614,112 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D91V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000454.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SOD1 | NM_000454.5 | c.272A>C | p.Asp91Ala | missense_variant | Exon 4 of 5 | ENST00000270142.11 | NP_000445.1 |
Ensembl
Frequencies
GnomAD3 genomes 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 Cov.: 30 AF XY: 0.000914 AC XY: 665AN XY: 727214
GnomAD4 genome 0.00119 AC: 181AN: 152290Hom.: 1 Cov.: 32 AF XY: 0.00158 AC XY: 118AN XY: 74468
ClinVar
Submissions by phenotype
Amyotrophic lateral sclerosis type 1 Pathogenic:7Uncertain:2
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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. -
Variant summary: SOD1 c.272A>C (p.Asp91Ala), also referred to as p.D90A in the literature, results in a non-conservative amino acid change located in the superoxide dismutase, copper/zinc binding domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 251472 control chromosomes in the gnomAD database, including 2 homozygotes. c.272A>C has been reported in the literature in multiple homozygous individuals affected with Amyotrophic Lateral Sclerosis (ALS) from families where the disorder is inherited in an autosomal recessive pattern, the majority of whom are of Scandinavian ancestry. Although the variant has been found to segregate with ALS in several of these families (e.g. Anderson_1995), there are also kindreds where the variant is only found in affected individuals from one branch of the family, while affected individuals from another branch do not have the variant (e.g. Felbecker_2010). Additionally, unaffected homozygous individuals have been reported in at least one family, suggesting reduced penetrance (e.g. Khoris_2000). The variant has also been reported in the heterozygous state in multiple individuals with autosomal dominant ALS (e.g. Robberecht_1996, Khoris_2000, Berdynski_2022). It has been found that families with autosomal recessive inheritance share the same founder haplotype, whereas several founders exist for those with the variant who exhibit an autosomal dominant pattern of inheritance (Al-Chalabi_1998). Altogether, these data indicate that the variant is likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (e.g. Anderson_1995, Lindberg_2002, Jonsson_2002, Prudencio_2009, Chen_2023). While the variant does not appear to negatively affect Cu-Zn-SOD activity, in at least two studies it has been found to result in significantly increased protein aggregation compared to the wild type protein (e.g. Prudencio_2009, Chen_2023). The following publications have been ascertained in the context of this evaluation (PMID: 9817920, 7647793, 34996976, 36376198, 20460594, 12270693, 10809943, 12482932, 19483195, 8909456). ClinVar contains an entry for this variant (Variation ID: 14766). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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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). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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
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. -
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SOD1: PM1, PM5, PS4:Moderate, PM2:Supporting, PP2, PP4, PS3:Supporting -
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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 Pathogenic:2
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This sequence change in SOD1 is predicted to replace aspartic acid with alanine at codon 91, p.(Asp91Ala). Historically this variant is known as p.(Asp90Ala) or p.D90A. The apartic acid residue is weakly conserved (100 vertebrates, UCSC), and is located in the Sod Cu domain. There is a large physicochemical difference between aspartic acid and alanine. The highest population minor allele frequency in gnomAD v2.1 is 1.2% (298/25,122 alleles, 3 homozygotes) in the Finnish population. Whereas, the highest continental population minor allele frequency in gnomAD v2.1 is 0.07% (96/129,186 alleles, 1 homozygote) in the European (non-Finnish) population. The homozygous individuals are absent from the non-neuro cohort in gnomAD v2.1. The variant is one of the most commonly reported SOD1 variants associated with amyotrophic lateral sclerosis (ALS) and is a Scandinavian founder, which shows both autosomal dominant and recessive patterns in different populations (PMID: 9817920, 12442272). The prevalence of the heterozygous variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 2.82, 95% CI: 1.40-5.67) (PMID: 19965850, 23100398, 28105640, 28222900, 28430856, 28444446; gnomAD v2.1 European non-Finnish non-neuro cohort). This variant has been detected in the homozygous state in many individuals with ALS and compound heterozygous with a second allele in at two affected families (PMID: 7647793, 11220750, 34668453). The recessive and dominant kindreds reported with the variant share a rare haplotype, however a recessive founder arose subsequently through a recombination event. The homozygous phenotype is characterised by prolonged survival and slow progression of disease, whereas the affected heterozygous phenotypes can vary (PMID: 12442272). In recessive kindreds segregation with ALS is reported in homozygous individuals and heterozygous individuals are unaffected (PMID: 7647793, 12442272). Whereas, in dominant kindreds segregation of the heterozygous variant with disease is reported with incomplete penetrance (PMID: 8909456, 10809943). A homozygous mouse model recapitulates the human ALS phenotype (PMID: 17146286). Multiple lines of computational evidence have conflicting predictions for the missense substitution (5/6 algorithms predict benign). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS3, PP1_Strong, PM3, PS4_Supporting. -
Amyotrophic lateral sclerosis 1, autosomal recessive Pathogenic:1
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SOD1-related disorder Pathogenic:1
The SOD1 c.272A>C variant is predicted to result in the amino acid substitution p.Asp91Ala. The c.272A>C change, previously described as p.Asp90Ala using legacy nomenclature, is a known founder variant found within the Scandinavian population and has previously been reported in autosomal recessive amyotrophic lateral sclerosis (ALS, Andersen et al. 1995. PubMed ID: 7647793; Gellera et al. 2001. PubMed ID: 11369193; Hand et al. 2001. PubMed ID: 11220750; Felbecker et al. 2010. PubMed ID: 20460594). In general, individuals who are homozygous for the c.272A>C variant present with longer duration of disease compared to autosomal dominant SOD1 mediated ALS (Tripolszki et al. 2017. PubMed ID: 28222900; Luisa Conforti et al. 2009. PubMed ID: 18608106). Heterozygous individuals have been reported in a few cases with some individuals presenting with atypical ALS (Origone et al. 2009. PubMed ID: 19922148; Dalla Bella et al. 2014. PubMed ID: 24591457; Khoris et al. 2000. PubMed ID: 10809943). This variant is reported in 1.2% of alleles in individuals of European (Finnish) descent in gnomAD; however, in the general population, its allele frequency is approximately 0.074%. This variant is interpreted as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at