rs121912446

Positions:

• chr21-31668547-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000454.5(SOD1):​c.434T>C​(p.Leu145Ser) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L145F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.49

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 18 ACMG points.

• PM1: In a strand (size 6) in uniprot entity SODC_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr21-31668548-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 21-31668547-T-C is Pathogenic according to our data. Variant chr21-31668547-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 14768.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	c.434T>C	p.Leu145Ser	missense_variant	5/5	ENST00000270142.11	NP_000445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOD1	ENST00000270142.11	c.434T>C	p.Leu145Ser	missense_variant	5/5	1	NM_000454.5	ENSP00000270142	P1
SOD1	ENST00000389995.4	c.377T>C	p.Leu126Ser	missense_variant	5/5	3		ENSP00000374645
SOD1	ENST00000470944.1	n.1362T>C		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2022	ClinVar contains an entry for this variant (Variation ID: 14768). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7496169, 9029070, 23062701, 27978769). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 145 of the SOD1 protein (p.Leu145Ser). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SOD1 function (PMID: 19483195, 23280792). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SOD1: PM1, PM2, PM5, PS4:Moderate, PP2, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2016	- -

Abnormal central motor function Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

SOD1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 20, 2024

The SOD1 c.434T>C variant is predicted to result in the amino acid substitution p.Leu145Ser. This variant, previously referred to as p.Leu144Ser using legacy nomenclature, has been reported to be causative for amyotrophic lateral sclerosis (ALS, Sapp et al. 1995. PubMed ID: 7496169; Alavi et al. 2013. PubMed ID: 23062701; Chadi et al. 2017 PubMed ID: 27978769; Cudkowicz et al. 1997. PubMed ID: 9029070). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been consistently classified as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/14768/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.96
Sift	Benign	0.031	D;D
Sift4G	Uncertain	0.056	T;T
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.93		Gain of disorder (P = 0.0012);.;
MVP		1.0
MPC		2.7
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.98

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: rs121912446; hg19: chr21-33040860;