Menu
GeneBe

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 Pathogenic.

Frequency

Genomes: ūĚĎď 0.0012 ( 1 hom., cov: 32)
Exomes ūĚĎď: 0.00093 ( 3 hom. )

Consequence

SOD1
NM_000454.5 missense

Scores

3
5
10

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:4

Conservation

PhyloP100: 0.308
Variant links:
Genes affected
SOD1 (HGNC:11179): (superoxide dismutase 1) The protein encoded by this gene binds copper and zinc ions and is one of two isozymes responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic protein, acting as a homodimer to convert naturally-occuring but harmful superoxide radicals to molecular oxygen and hydrogen peroxide. The other isozyme is a mitochondrial protein. In addition, this protein contains an antimicrobial peptide that displays antibacterial, antifungal, and anti-MRSA activity against E. coli, E. faecalis, S. aureus, S. aureus MRSA LPV+, S. agalactiae, and yeast C. krusei. Mutations in this gene have been implicated as causes of familial amyotrophic lateral sclerosis. Rare transcript variants have been reported for this gene. [provided by RefSeq, Jul 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000454.5
PM5
Other missense variant is known to change same aminoacid residue: Variant chr21-31667290-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1802147.Status of the report is criteria_provided_single_submitter, 1 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.17195162).
BS2
High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOD1NM_000454.5 linkuse as main transcriptc.272A>C p.Asp91Ala missense_variant 4/5 ENST00000270142.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOD1ENST00000270142.11 linkuse as main transcriptc.272A>C p.Asp91Ala missense_variant 4/51 NM_000454.5 P1
ENST00000609934.1 linkuse as main transcript upstream_gene_variant

Frequencies

GnomAD3 genomes
AF:
0.00119
AC:
181
AN:
152172
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.0128
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000573
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.00143
AC:
360
AN:
251472
Hom.:
2
AF XY:
0.00134
AC XY:
182
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000867
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000588
Gnomad FIN exome
AF:
0.0115
Gnomad NFE exome
AF:
0.000730
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.000928
AC:
1357
AN:
1461822
Hom.:
3
Cov.:
30
AF XY:
0.000914
AC XY:
665
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000591
Gnomad4 FIN exome
AF:
0.0108
Gnomad4 NFE exome
AF:
0.000616
Gnomad4 OTH exome
AF:
0.000563
GnomAD4 genome
AF:
0.00119
AC:
181
AN:
152290
Hom.:
1
Cov.:
32
AF XY:
0.00158
AC XY:
118
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.0128
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000417
Hom.:
0
Bravo
AF:
0.000302
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.00112
AC:
136
EpiCase
AF:
0.000545
EpiControl
AF:
0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:13Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:6Uncertain:2
Likely pathogenic, criteria provided, single submitterclinical testing3billionFeb 23, 2023The 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. -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 10, 2007- -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMar 30, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeDec 18, 2023This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoDec 12, 2016- -
Pathogenic, no assertion criteria providedclinical testingInstitute of Human Genetics, Cologne UniversityApr 25, 2018- -
Likely pathogenic, criteria provided, single submitterresearchSuna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc UniversityMar 31, 2020- -
Uncertain significance, criteria provided, single submitterclinical testingMGZ Medical Genetics CenterSep 13, 2021- -
not provided Pathogenic:3Uncertain:2
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 22, 2020This 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). -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJan 29, 2016The 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024SOD1: PM1, PM5, PS4:Moderate, PM2:Supporting, PP2, PP4, PS3:Supporting -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicOct 14, 2019- -
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital T√ľbingenOct 23, 2020- -
Amyotrophic lateral sclerosis Pathogenic:2
Pathogenic, criteria provided, single submitterresearchDept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital TrustJan 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingMolecular Genetics, Royal Melbourne HospitalMar 30, 2023This 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
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 10, 2007- -
SOD1-related condition Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 16, 2024The 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). Patients homozygous for the c.272A>C change 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 with the c.272A>C variant have been reported in a few cases with some patients 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. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Uncertain
0.025
T
BayesDel_noAF
Pathogenic
0.17
Cadd
Benign
14
Dann
Benign
0.84
DEOGEN2
Pathogenic
0.96
D;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.22
N
LIST_S2
Uncertain
0.86
D;D
MetaRNN
Benign
0.17
T;T
MetaSVM
Pathogenic
1.2
D
MutationAssessor
Uncertain
2.3
M;.
MutationTaster
Benign
4.0e-10
A;A
PrimateAI
Benign
0.27
T
PROVEAN
Uncertain
-2.4
N;N
REVEL
Uncertain
0.56
Sift
Benign
0.10
T;T
Sift4G
Benign
0.090
T;T
Polyphen
0.0
B;.
Vest4
0.64
MVP
0.89
MPC
1.4
ClinPred
0.044
T
GERP RS
-5.9
Varity_R
0.60
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs80265967; hg19: chr21-33039603; API