chr21-31667320-A-G

Variant names:

• chr21-31667320-A-G
• rs121912439
• NM_000454.5:c.302A>G

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000454.5(SOD1):​c.302A>G​(p.Glu101Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 0.611
• Publications: 25 publications found

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]

SOD1 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic tetraplegia and axial hypotonia, progressive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273271 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-31667319-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 574319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 96 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.83817 (below the threshold of 3.09). Trascript score misZ: 1.2198 (below the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 1, amyotrophic lateral sclerosis, spastic tetraplegia and axial hypotonia, progressive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-31667320-A-G is Pathogenic according to our data. Variant chr21-31667320-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000454.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	NM_000454.5	MANE Select	c.302A>G	p.Glu101Gly	missense	Exon 4 of 5	NP_000445.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOD1	ENST00000270142.11	TSL:1 MANE Select	c.302A>G	p.Glu101Gly	missense	Exon 4 of 5	ENSP00000270142.7
	SOD1	ENST00000389995.4	TSL:3	c.245A>G	p.Glu82Gly	missense	Exon 4 of 5	ENSP00000374645.4
	SOD1	ENST00000470944.1	TSL:2	n.1230A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000262 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:3

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 101 of the SOD1 protein (p.Glu101Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant SOD1-related conditions (PMID: 28105640). ClinVar contains an entry for this variant (Variation ID: 14761). 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 disruptive. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 20399791, 23280792, 26362407). This variant disrupts the p.Glu101 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8875253, 15258228, 20540686, 22292843). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Mar 21, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by clinical laboratories in ClinVar, and reported in the literature in heterozygous individuals with a type of motor neuron disease, predominantly amyotrophic lateral sclerosis (PMID: 28089114, 32789025, 23869403); Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Glu101Lys) has been classified as pathogenic by clinical laboratories in ClinVar. Additional information: Variant is predicted to result in a missense amino acid change from glutamic acid to glycine; This variant is heterozygous; This gene is associated with both recessive and dominant disease (OMIM); Variant is located in the annotated copper/zinc superoxide dismutase domain (DECIPHER); Missense variant with inconclusive in silico prediction and uninformative conservation; Loss of function and toxic gain of function are known mechanisms of disease in this gene and are associated with amyotrophic lateral sclerosis 1 (MIM#105400). Missense variants have been described with both a loss of function and toxic gain of function effect, where protein expression and activity is reduced, but residual protein results in misfolded aggregates (OMIM, PMID: 34721532); The autosomal dominant amyotrophic lateral sclerosis associated with this gene has incomplete penetrance (PMID: 38811997); Inheritance information for this variant is not currently available in this individual.

Jul 24, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Motor neuron disease Pathogenic:1

Aug 31, 2016

Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

not provided Pathogenic:1

Jul 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that the variant increases aggregation of the SOD1 protein and decreases protein stability (Prudencio et al., 2009; Vassall et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 7635196, 23280792, 20399791, 18951903, 21257910, 26362407, 8891072, 32006803, 28105640, 28089114, 32789025, 7624031, 8446170, 19483195)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.32	N
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.61
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.63
Sift	Benign	0.074	T
Sift4G	Benign	0.15	T
Polyphen		0.44	B
Vest4		0.71
MutPred		0.75		Loss of stability (P = 0.0473)
MVP		0.99
MPC		2.1
ClinPred		0.87	D
GERP RS		3.8
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.71
gMVP		0.86
Mutation Taster		=13/87	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912439; hg19: chr21-33039633;