rs121912441

Positions:

chr21-31667359-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The ENST00000270142.11(SOD1):c.341T>C(p.Ile114Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,611,670 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I114M) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SOD1
ENST00000270142.11 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.49

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000270142.11

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-31667360-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2018599.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 21-31667359-T-C is Pathogenic according to our data. Variant chr21-31667359-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOD1	NM_000454.5 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	4/5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SOD1	ENST00000270142.11 linkuse as main transcript	c.341T>C	p.Ile114Thr	missense_variant	4/5	1	NM_000454.5	ENSP00000270142	P1
SOD1	ENST00000389995.4 linkuse as main transcript	c.284T>C	p.Ile95Thr	missense_variant	4/5	3		ENSP00000374645
SOD1	ENST00000470944.1 linkuse as main transcript	n.1269T>C		non_coding_transcript_exon_variant	4/5	2
SOD1	ENST00000476106.5 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251478

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1459444

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 1

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 09, 2024	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and toxic gain of function are known mechanisms of disease in this gene and are associated with amyotrophic lateral sclerosis 1 (MIM#105400). Missense variants have been described with both a loss- and toxic gain of function effect, where protein expression and activity is reduced, but residual protein results in misfolded aggregates (OMIM, PMID: 34721532). (I) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from an isoleucine to a threonine. (I) 0251 - Variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Ile114Pro) has been previously reported in an individual with amyotrophic lateral sclerosis 1 (PMID: 16291929). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported eight times as pathogenic and once as likely pathogenic (ClinVar) and has been reported in many individuals with amyotrophic lateral sclerosis 1 (PMIDs: 28430856, 28105640). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change in SOD1 is predicted to replace isoleucine with threonine at codon 114, p.(Ile114Thr) (also known as p.Ile113Thr). The isoleucine residue is highly conserved (100 vertebrates, UCSC), and is located in copper/zinc superoxide dismutase domain. There is a moderate physicochemical difference between isoleucine and threonine. The highest population minor allele frequency in gnomAD v2.1 is 0.01% (12/113,758 alleles) in the European (non-Finnish) population. The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (odds ratio 200, 95% CI: 23.3-1711; cases - PMID: 28430856; controls - non-neuro non-Finnish European cohort gnomAD v2.1). It is the most common pathogenic SOD1 variant and has been associated with incomplete penetrance. The variant has been reported to segregate with amyotrophic lateral sclerosis (ALS) in multiple families, with at least two founder events identified in the Australian population (PMID: 32789025). Expression of the variant in human embryonic stem cell-derived motor neurones resulted in motor neurones with characteristics of ALS-related degeneration (PMID: 19259395). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 114 of the SOD1 protein (p.Ile114Thr). This variant is present in population databases (rs121912441, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 2517465, 7673954, 7997024, 17543992). ClinVar contains an entry for this variant (Variation ID: 197145). 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: 1259395, 19483195, 21549128, 23726301, 26362407). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 07, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 17, 2023	Variant summary: SOD1 c.341T>C (p.Ile114Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251478 control chromosomes. c.341T>C has been reported in the literature in multiple individuals affected with Amyotrophic Lateral Sclerosis (Pfister_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence and showed that this mutation affects cell morphology and viability (Karumbayaram_2009). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2020	Functional studies demonstrate that the I114T variant results in aberrant interaction between glial and neuronal cells, protein misfolding, as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (Kokubo et al., 1999; Ferri et al., 2004;Ip ei al., 2011 ).; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23736301, 10732812, 7643359, 30985904, 28430856, 23280792, 19259395, 15208263, 19483195, 23291526, 10593307, 28089114, 26707039, 25588603, 8446170, 23873540, 23773010, 16423367, 17543992, 30887850, 31579943, 30805795, 21549128, 26362407, 32789025) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 02, 2020	This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (http://gnomad.broadinstitute.org). This variant has been reported in multiple families with reduced penetrance and variable expressivity of disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiments demonstrate this variant increases protein aggregation (PMID 19483195), as well as accumulation of neurofilaments and mutant SOD1 protein in neuronal cells (PMID 12358759). Computational tools predict that this variant is damaging. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 28, 2023	PP3, PM2_moderate, PS3, PS4_moderate -

Motor neuron disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Centre for Genomic and Experimental Medicine, University of Edinburgh

Aug 31, 2016

- -

SOD1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The SOD1 c.341T>C variant is predicted to result in the amino acid substitution p.Ile114Thr. This variant, previously described as p.Ile113Thr using legacy nomenclature, has been documented to be causative for amyotrophic lateral sclerosis (ALS, Rosen et al. 1993. PubMed ID: 8446170; Nakamura et al. 2014. PubMed ID: 23773010; Kikugawa et al. 1997. PubMed ID: 10732812; Morgan et al. 2017. PubMed ID: 28430856). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been classified as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/197145/). This variant is interpreted as pathogenic. -

Spastic tetraplegia and axial hypotonia, progressive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

provider interpretation

Solve-RD Consortium

Jun 01, 2022

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.8

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

1.0

D;.

Vest4

0.88

MutPred

0.88

Loss of stability (P = 0.0214);.;

MVP

1.0

MPC

2.0

ClinPred

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Varity_R

0.91

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over