rs121912446

Variant names:

• chr21-31668547-T-C
• rs121912446
• NM_000454.5:c.434T>C

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.434T>C​(p.Leu145Ser) variant causes a missense change involving the alteration of a 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. L145F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.49
• Publications: 24 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

ACMG classification

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

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr21-31668548-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 586637.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, 0.993
• PP5: Variant 21-31668547-T-C is Pathogenic according to our data. Variant chr21-31668547-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 14768.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.434T>C	p.Leu145Ser	missense	Exon 5 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.434T>C	p.Leu145Ser	missense	Exon 5 of 5	ENSP00000270142.7
	SOD1	ENST00000389995.4	TSL:3	c.377T>C	p.Leu126Ser	missense	Exon 5 of 5	ENSP00000374645.4
	SOD1	ENST00000470944.1	TSL:2	n.1362T>C		non_coding_transcript_exon	Exon 5 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:5

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 14, 2024

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP2,PP3(Moderate),PM1,PS4,PS3(Supporting),PM5

May 13, 2025

Clinical Omics and Informatics (COIN) Unit, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Variant is absent from gnomAD v4 (coverage >20X confirmed) and the AGVD database. PP3_Strong: Revel score is 0.96. PM1 Met: Variant is located in a critical and well-established functional domain. Residue is adjacent to the active site (Arg143) consistent with other pathogenic SOD1 variants (PMID:7496169). PM5 Met: Pathogenic missense variants reported at same amino acid (PMID: 7496169, 23062701). PS3_Supporting: Study demonstrates that p.Leu145Ser shares the toxic conformational property seen in pathogenic SOD1 variants, indicating a damaging effect on the protein (PMID:23280792). PS4_Met: ≥10 unrelated probands with consistent phenotype for disorder (VCV000014768.33, PMID:23062701;9029070;7496169;27978769).

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 145 of the SOD1 protein (p.Leu145Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7496169, 9029070, 23062701, 27978769). ClinVar contains an entry for this variant (Variation ID: 14768). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SOD1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 23280792). For these reasons, this variant has been classified as Pathogenic.

Sep 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:2

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOD1: PM1, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting

May 03, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SOD1-related disorder Pathogenic:1

Mar 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOD1 c.434T>C variant is predicted to result in the amino acid substitution p.Leu145Ser. This variant, previously referred to as p.Leu144Ser using legacy nomenclature, has been reported to be causative for amyotrophic lateral sclerosis (ALS, Sapp et al. 1995. PubMed ID: 7496169; Alavi et al. 2013. PubMed ID: 23062701; Chadi et al. 2017 PubMed ID: 27978769; Cudkowicz et al. 1997. PubMed ID: 9029070). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14768/). This variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.96
Sift	Benign	0.031	D
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Gain of disorder (P = 0.0012)
MVP		1.0
MPC		2.7
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.98
Mutation Taster		=14/86	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: rs121912446; hg19: chr21-33040860;