rs121912437

Variant names:

• chr21-31667298-G-A
• rs121912437
• NM_000454.5:c.280G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-31667298-G-A
• chr21-31667298-G-C
• chr21-31667298-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000454.5(SOD1):​c.280G>A​(p.Gly94Ser) variant causes a missense change. 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. G94D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.94

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]

ENSG00000273271 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain Superoxide dismutase [Cu-Zn] (size 152) in uniprot entity SODC_HUMAN there are 55 pathogenic changes around while only 1 benign (98%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 21-31667298-G-A is Pathogenic according to our data. Variant chr21-31667298-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2634277.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5	c.280G>A	p.Gly94Ser	missense_variant	Exon 4 of 5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.280G>A	p.Gly94Ser	missense_variant	Exon 4 of 5	1	NM_000454.5	ENSP00000270142.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:1

Jun 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 94 of the SOD1 protein (p.Gly94Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 9455983, 23286750). This variant is also known as Gly93-->Ser, G93C. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOD1 protein function. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 21257910, 26362407). This variant disrupts the p.Gly94 amino acid residue in SOD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8004110, 9029070, 12482932, 16476815, 18273717, 19483195, 20577002, 21120636, 24325798, 28089114). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -

SOD1-related disorder Pathogenic:1

Sep 25, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOD1 c.280G>A variant is predicted to result in the amino acid substitution p.Gly94Ser. This variant, previously described as p.Gly93Ser using legacy nomenclature, has been reported in patients with amyotrophic lateral sclerosis (see for example - Kawata et al. 1997. PubMed ID: 9455983). We have also observed this variant in three ALS patients tested at PreventionGenetics. Several other missense changes at the same amino acid position, c.281G>C (p.Gly94Ala), c.281G>A (p.Gly94Asp), c.280G>C (p.Gly94Arg), c.281G>T (p.Gly94Val), and c.280>T (p.Gly94Cys), have all been reported to be causative for ALS (Rosen. 1993. PubMed ID: 8446170; Esteban. 1994. PubMed ID: 7951252; Luigetti et al. 2009. PubMed ID: 19922144; Black et al. 2017. PubMed ID: 28089114; Hosler et al. 1996. PubMed ID: 8938700). Functional studies found this variant results in SOD1 protein aggregation (Prudencio et al. 2009. PubMed ID: 19483195; Vassall et al. 2011. PubMed ID: 21257910). This variant has not been reported in a large population database, indicating this variant is rare. Missense changes not present in the gnomAD database are frequently seen in documented pathogenic variants within the SOD1 gene. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.028	D;D
Sift4G	Uncertain	0.043	D;D
Polyphen		0.86	P;.
Vest4		0.85
MutPred		0.90		Gain of phosphorylation at G94 (P = 0.0556);.;
MVP		0.99
MPC		2.3
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.7
Varity_R		0.90
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121912437; hg19: chr21-33039611;