Menu
GeneBe

rs121912442

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000454.5(SOD1):c.14C>T(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,542 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A5S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SOD1
NM_000454.5 missense

Scores

10
8
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 5.94
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 Pathogenic. Variant got 18 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr21-31659782-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 873321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.995
PP5
Variant 21-31659783-C-T is Pathogenic according to our data. Variant chr21-31659783-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14763.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOD1NM_000454.5 linkuse as main transcriptc.14C>T p.Ala5Val missense_variant 1/5 ENST00000270142.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOD1ENST00000270142.11 linkuse as main transcriptc.14C>T p.Ala5Val missense_variant 1/51 NM_000454.5 P1
SOD1ENST00000389995.4 linkuse as main transcriptc.14C>T p.Ala5Val missense_variant, splice_region_variant 1/53
SOD1ENST00000470944.1 linkuse as main transcriptn.75C>T non_coding_transcript_exon_variant 1/52
SOD1ENST00000476106.5 linkuse as main transcriptn.91C>T non_coding_transcript_exon_variant 1/55

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000359
AC:
9
AN:
250494
Hom.:
0
AF XY:
0.0000295
AC XY:
4
AN XY:
135690
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000796
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461542
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
727104
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000308
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:4Other:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 12, 2009- -
not provided, no classification providedphenotyping onlyGenomeConnect, ClinGen-Variant interpretted as Pathogenic and reported on 08-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 29, 2024This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the SOD1 protein (p.Ala5Val). This variant is present in population databases (rs121912442, gnomAD 0.008%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7951249, 8351519, 19176896, 19618436). This variant is also known as p.Ala4Val. ClinVar contains an entry for this variant (Variation ID: 14763). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 12482932, 19259395, 19483195, 19800308, 20404329, 21549128, 22094223). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGM-The missense variant c.14C>T (p.Ala5Val) has been reported in many individuals affected with familial amyotrophic lateral sclerosis (FALS) (Deng et al. 1993, Salameh et al. 2009) and has been reported to segregate with disease in multiple families (Deng et al. 1993). Experimental studies have shown that this missense change impacts SOD1 protein structure and leads to mis-folding and aggregation (Prudencio et al. 2011). It has also been shown to impact cell survival in human embryonic stem cell-derived motor neurons (Karumbayaram et al. 2009). The p.Ala5Val variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.004%. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ala at position 5 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala5Val in SOD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsJun 29, 2023A5V is the most common ALS-associated variant in North America (PMID: 19176896, 18055113, 9029070), therefore, the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant is also referred to as A4V in published literature. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 20184893, 19635794, 16945901, 23291526) -
Pathogenic, criteria provided, single submitterclinical testingGeneDxFeb 18, 2020Functional studies demonstrate a 50% reduction in activity of cytosolic SOD1 in patients with A5V compared to unaffected individuals (Rosen et al., 1994; Lindberg et al., 2002); Additional published functional studies demonstrate that the variant alters protein stability and activity, results in reduced nuclear localization, and leads to formation of inclusions (Brasil et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28884318, 8351519, 19618436, 31781168, 29564924, 31134679, 19176896, 26362407, 26298469, 26084641, 12482932, 21257910, 16945901, 20404910, 23118898, 23784844, 21930207, 22094223, 18319614, 24793051, 20184893, 21549128, 20399791, 23291526, 25096579, 23760509, 20404329, 19635794, 19196430, 24134191, 7951249, 19483195, 22589106, 19259395, 19751676, 23280792, 19800308, 26413785) -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 28, 2014- -
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicFeb 23, 2021PS3, PS4, PM2, PP3 -
SOD1-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesSep 12, 2023The SOD1 c.14C>T variant is predicted to result in the amino acid substitution p.Ala5Val. This variant, previously described as p.Ala4Val using legacy nomenclature, has been repeatedly reported to be causative for amyotrophic lateral sclerosis (Deng et al. 1993. PubMed ID: 8351519; Saeed et al. 2009. PubMed ID: 19176896). The c.14C>T variant has also been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14763/). We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.42
Cadd
Pathogenic
32
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Pathogenic
0.99
D;T
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;.
MutationTaster
Benign
0.069
A;A
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-3.2
D;N
REVEL
Pathogenic
0.85
Sift
Uncertain
0.0050
D;T
Sift4G
Uncertain
0.014
D;T
Polyphen
1.0
D;.
Vest4
0.65
MutPred
0.94
Gain of methylation at K4 (P = 0.0344);Gain of methylation at K4 (P = 0.0344);
MVP
0.98
MPC
1.9
ClinPred
0.94
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.79
gMVP
0.89

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: rs121912442; hg19: chr21-33032096; API