rs76731700

chr21-31667319-G-Achr21-31667319-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_000454.5(SOD1):c.301G>A(p.Glu101Lys) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.48

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 15 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 chr21-31667320-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777
• PP5: Variant 21-31667319-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD1	NM_000454.5	c.301G>A	p.Glu101Lys	missense_variant	4/5	ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11	c.301G>A	p.Glu101Lys	missense_variant	4/5	1	NM_000454.5	P1
SOD1	ENST00000389995.4	c.244G>A	p.Glu82Lys	missense_variant	4/5	3
SOD1	ENST00000470944.1	n.1229G>A		non_coding_transcript_exon_variant	4/5	2
SOD1	ENST00000476106.5	n.564G>A		non_coding_transcript_exon_variant	5/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Dept. of Medical Genetics, Telemark Hospital Trust, Telemark Hospital Trust

Jan 01, 2022

- -

Amyotrophic lateral sclerosis type 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 101 of the SOD1 protein (p.Glu101Lys). 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: 15258228, 20460594, 20540686, 29411640; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 382G>A (E100K). ClinVar contains an entry for this variant (Variation ID: 574319). 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 not expected to disrupt SOD1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 23280792, 25600987). 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: 19483195, 20399791, 23280792, 26362407, 28105640). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 07, 2021

This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. In some published literature, this variant is referred to as E100K. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant increased propensity of the protein to form aggregates (PMID: 19483195, 25600987). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	15
Dann	Benign	0.66
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.18	N
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	-0.10	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.71	N;N
REVEL	Uncertain	0.59
Sift	Benign	0.45	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0	B;.
Vest4		0.36
MutPred		0.76		Gain of ubiquitination at E101 (P = 0.0198);.;
MVP		0.95
MPC		1.3
ClinPred		0.060	T
GERP RS		1.1
Varity_R		0.35
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs76731700; hg19: chr21-33039632;