rs121912439

chr21-31667320-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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:4
• Conservation: PhyloP100: 0.611

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 [Likely_pathogenic]. Clinvar id is 574319.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 21-31667320-A-G is Pathogenic according to our data. Variant chr21-31667320-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 14761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD1	NM_000454.5	c.302A>G	p.Glu101Gly	missense_variant	4/5	ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11	c.302A>G	p.Glu101Gly	missense_variant	4/5	1	NM_000454.5	P1
SOD1	ENST00000389995.4	c.245A>G	p.Glu82Gly	missense_variant	4/5	3
SOD1	ENST00000470944.1	n.1230A>G		non_coding_transcript_exon_variant	4/5	2
SOD1	ENST00000476106.5	n.565A>G		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000426 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 17, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 24, 1995	- -

Motor neuron disease Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2023

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 v4.3

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;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.7	M;.
MutationTaster	Benign	2.8e-7	A;A
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.63
Sift	Benign	0.074	T;T
Sift4G	Benign	0.15	T;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

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

Other links and lift over

dbSNP: rs121912439; hg19: chr21-33039633;