rs121912443

chr21-31663857-A-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 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:6
• Conservation: PhyloP100: 8.39

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 16 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, 1 uncertain in NM_000454.5
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 14764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-31663857-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOD1	NM_000454.5	c.140A>G	p.His47Arg	missense_variant	2/5	ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11	c.140A>G	p.His47Arg	missense_variant	2/5	1	NM_000454.5	P1
SOD1	ENST00000389995.4	c.83A>G	p.His28Arg	missense_variant	2/5	3
SOD1	ENST00000470944.1	n.1068A>G		non_coding_transcript_exon_variant	2/5	2
SOD1	ENST00000476106.5	n.403A>G		non_coding_transcript_exon_variant	3/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	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). 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 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 18, 2000	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Apr 20, 2023	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

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 18, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2016	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. -

Amyotrophic lateral sclerosis Pathogenic:1

Pathogenic, criteria provided, single submitter

research

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

Jan 01, 2022

- -

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;.
MutationTaster	Benign	1.0	A;A
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

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: rs121912443; hg19: chr21-33036170;