rs80265967

chr21-31667290-A-Cchr21-31667290-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PM1 PM5 BP4_Moderate BS2

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: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (3 hom.)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:4
• Conservation: PhyloP100: 0.308

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]

(HGNC:):

ACMG classification

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
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: 181 AN: 152172 Hom.: 1 Cov.: 32

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

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

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

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:14 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:7 Uncertain:2

Likely pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 10, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	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. -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Cologne University	Apr 25, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 12, 2016	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 06, 2024	Variant summary: SOD1 c.272A>C (p.Asp91Ala) 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. This frequency is not significantly higher than estimated for a pathogenic variant in SOD1 causing Amyotrophic Lateral Sclerosis Type 1 (0.0014 vs ND), allowing no conclusion about variant significance. c.272A>C has been reported in the literature in multiple individuals affected with Amyotrophic Lateral Sclerosis Type 1. In families with this variant, 28 transmissions of the variant allele and 10 transmissions of the reference allele to affected individuals was reported. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. ClinVar contains an entry for this variant (Variation ID: 14766). Based on the evidence outlined above, the variant was classified as pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 13, 2021	- -

not provided Pathogenic:3 Uncertain:2

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	Athena Diagnostics	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 14, 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	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SOD1: PM1, PM5, PS4:Moderate, PM2:Supporting, PP2, PP4, PS3:Supporting -

Amyotrophic lateral sclerosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	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. -
Pathogenic, criteria provided, single submitter	research	Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust	Jan 01, 2022	- -

Amyotrophic lateral sclerosis 1, autosomal recessive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 10, 2007

- -

SOD1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 16, 2024

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). 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

Other links and lift over

dbSNP: rs80265967; hg19: chr21-33039603;