rs1555836720

Positions:

• chr21-31666499-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000454.5(SOD1):​c.220G>A​(p.Gly74Arg) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 9.01

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD1	NM_000454.5	c.220G>A	p.Gly74Arg	missense_variant	3/5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.220G>A	p.Gly74Arg	missense_variant	3/5	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000389995.4	c.163G>A	p.Gly55Arg	missense_variant	3/5	3		ENSP00000374645.4
SOD1	ENST00000470944.1	n.1148G>A		non_coding_transcript_exon_variant	3/5	2
SOD1	ENST00000476106.5	n.483G>A		non_coding_transcript_exon_variant	4/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SOD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 74 of the SOD1 protein (p.Gly74Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. -

SOD1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2024

The SOD1 c.220G>A variant is predicted to result in the amino acid substitution p.Gly74Arg. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. A different missense change impacting the same amino acid (c.221G>A, p.Gly74Glu) has been reported in an individual with spinal onset amyotrophic lateral sclerosis (ALS, Table 2, Lamp et al. 2018. PubMed ID: 29525178). In general, SOD1 has a low rate of benign missense variation; and missense variants are the most common mechanism of SOD1-related ALS (ClinVar, HGMD). Although we suspect that the c.220G>A (p.Gly74Arg) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;.
Vest4		0.57
MutPred		0.55		Loss of ubiquitination at K71 (P = 0.0341);.;
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555836720; hg19: chr21-33038812;