21-31663857-A-G

Variant names:

• chr21-31663857-A-G
• rs121912443
• NM_000454.5:c.140A>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000454.5(SOD1):​c.140A>G​(p.His47Arg) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.39
• Publications: 279 publications found

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 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spastic tetraplegia and axial hypotonia, progressive

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 96 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.83817 (below the threshold of 3.09). Trascript score misZ: 1.2198 (below the threshold of 3.09). GenCC associations: The gene is linked to amyotrophic lateral sclerosis type 1, amyotrophic lateral sclerosis, spastic tetraplegia and axial hypotonia, progressive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-31663857-A-G is Pathogenic according to our data. Variant chr21-31663857-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 14764.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	c.140A>G	p.His47Arg	missense_variant	Exon 2 of 5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.140A>G	p.His47Arg	missense_variant	Exon 2 of 5	1	NM_000454.5	ENSP00000270142.7
SOD1	ENST00000389995.4	c.83A>G	p.His28Arg	missense_variant	Exon 2 of 5	3		ENSP00000374645.4
SOD1	ENST00000470944.1	n.1068A>G		non_coding_transcript_exon_variant	Exon 2 of 5	2
SOD1	ENST00000476106.5	n.403A>G		non_coding_transcript_exon_variant	Exon 3 of 5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:3

Jul 18, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 47 of the SOD1 protein (p.His47Arg). 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 (ALS) (PMID: 7836951, 8298637, 14506936, 22475618, 25025039). It has also been observed to segregate with disease in related individuals. This variant is also known as p.His46Arg. ClinVar contains an entry for this variant (Variation ID: 14764). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 7836951, 8298637, 10889018, 18951903, 19483195, 19635794). For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2023

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The His47Arg variant of SOD1 gene is the most frequent SOD1 mutation in Asian ALS patients (Arisato 2003, Tang 2019). The mutation first described in two Japanese ALS families and is found to be disruptive for protein function (Aoki 1994). -

not provided Pathogenic:2

Jun 27, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The H47R variant in the SOD1 gene, also reported as H46R due to alternate nomenclature, was initially found to co-segregate with a slowly progressive autosomal dominant form of amyotrophic lateral sclerosis in multiple affected individuals from two unrelated Japanese families (Aoki et al., 1993). The H47R variant has also been reported to co-segregate with a dominant form of hereditary motor neuropathy (Ostern et al., 2012; Hoyer et al., 2014). The H47R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The H47R variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. Functional studies demonstrate that results in a conformational change of the SOD1 protein resulting in aberrant binding activity (Fujisawa et al., 2012). We interpret H47R as a pathogenic variant. -

Jan 18, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was not 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. This variant is also referred to as p.His46Arg in published literature. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant was shown to impair the metal binding activity of the protein (PMID: 10889018, 19635794, 18951903). Computational tools predict that this variant is damaging. -

Amyotrophic lateral sclerosis Pathogenic:1

Jan 01, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

SOD1-related disorder Pathogenic:1

Mar 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SOD1 c.140A>G variant is predicted to result in the amino acid substitution p.His47Arg. This variant, previously referred to as p.His46Arg using legacy nomenclature, has been reported to be causative for ALS in the heterozygous state (Aoki et al. 1993, PubMed ID: 8298637; Niemann et al 2004. PubMed ID: 15258228). The c.140A>G variant has been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14764/). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.7	H;.
PhyloP100		8.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.5	D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0070	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.97		Loss of sheet (P = 0.0817);.;
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912443; hg19: chr21-33036170;