21-31659779-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000454.5(SOD1):c.10A>G(p.Lys4Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,554 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 (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SOD1
NM_000454.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.26

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]

SOD1 links:

SOD1-DT (HGNC:55683): (SOD1 divergent transcript)

SOD1-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a strand (size 7) in uniprot entity SODC_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000454.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.968

PP5

Variant 21-31659779-A-G is Pathogenic according to our data. Variant chr21-31659779-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2138372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOD1	NM_000454.5 link	c.10A>G	p.Lys4Glu	missense_variant	Exon 1 of 5	ENST00000270142.11	NP_000445.1
SOD1-DT	NR_187558.1 link	n.246T>C		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOD1	ENST00000270142.11 link	c.10A>G	p.Lys4Glu	missense_variant	Exon 1 of 5	1	NM_000454.5	ENSP00000270142.7	P00441
SOD1	ENST00000389995.4 link	c.10A>G	p.Lys4Glu	missense_variant	Exon 1 of 5	3		ENSP00000374645.4	H7BYH4
SOD1	ENST00000470944.1 link	n.71A>G		non_coding_transcript_exon_variant	Exon 1 of 5	2
SOD1	ENST00000476106.5 link	n.87A>G		non_coding_transcript_exon_variant	Exon 1 of 5	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727116

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1

Pathogenic:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 4 of the SOD1 protein (p.Lys4Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with amyotrophic lateral sclerosis (PMID: 18852346, 23898858, 32729725). This variant is also known as K3E. ClinVar contains an entry for this variant (Variation ID: 2138372). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SOD1 function (PMID: 23280792). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jul 14, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect on conformation of SOD1 proteins (Fujisawa et al., 2012); Also known as p.K3E; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23280792, 18852346, 34996976, 32729725, 23898858) -

SOD1-related disorder

Pathogenic:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOD1 c.10A>G variant is predicted to result in the amino acid substitution p.Lys4Glu. This variant has been reported in multiple unrelated individuals with amyotrophic lateral sclerosis (Takahashi et al. 2008. PubMed ID: 18852346; Kuźma-Kozakiewicz et al. 2013. PubMed ID: 23898858; Shibuya et al. 2020. PubMed ID: 32729725; Berdyński et al. 2022. PubMed ID: 34996976). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.2

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

D;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0060

D;T

Sift4G

Uncertain

0.017

D;T

Polyphen

0.82

P;.

Vest4

0.54

MutPred

0.83

Loss of ubiquitination at K4 (P = 0.0161);Loss of ubiquitination at K4 (P = 0.0161);

MVP

0.99

MPC

1.9

ClinPred

0.98

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.96

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over