chr21-31659783-C-T

Position:

• chr21-31659783-C-T

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.14C>T​(p.Ala5Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,542 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SOD1 NM_000454.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 5.94

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 chr21-31659782-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 873321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-31659783-C-T is Pathogenic according to our data. Variant chr21-31659783-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 14763.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.14C>T	p.Ala5Val	missense_variant	1/5	ENST00000270142.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOD1	ENST00000270142.11	c.14C>T	p.Ala5Val	missense_variant	1/5	1	NM_000454.5	P1
SOD1	ENST00000389995.4	c.14C>T	p.Ala5Val	missense_variant, splice_region_variant	1/5	3
SOD1	ENST00000470944.1	n.75C>T		non_coding_transcript_exon_variant	1/5	2
SOD1	ENST00000476106.5	n.91C>T		non_coding_transcript_exon_variant	1/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250494 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135690

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: 0.0000796

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461542 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727104

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000308 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 1 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the SOD1 protein (p.Ala5Val). This variant is present in population databases (rs121912442, gnomAD 0.008%). This missense change has been observed in individuals with autosomal dominant amyotrophic lateral sclerosis (PMID: 7951249, 8351519, 19176896, 19618436). This variant is also known as p.Ala4Val. ClinVar contains an entry for this variant (Variation ID: 14763). 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: 12482932, 19259395, 19483195, 19800308, 20404329, 21549128, 22094223). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 12, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.14C>T (p.Ala5Val) has been reported in many individuals affected with familial amyotrophic lateral sclerosis (FALS) (Deng et al. 1993, Salameh et al. 2009) and has been reported to segregate with disease in multiple families (Deng et al. 1993). Experimental studies have shown that this missense change impacts SOD1 protein structure and leads to mis-folding and aggregation (Prudencio et al. 2011). It has also been shown to impact cell survival in human embryonic stem cell-derived motor neurons (Karumbayaram et al. 2009). The p.Ala5Val variant is novel (not in any individuals) in 1000 Genomes and is present in the gnomAD exomes database with a frequency of 0.004%. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ala at position 5 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala5Val in SOD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Pathogenic and reported on 08-15-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 29, 2023	A5V is the most common ALS-associated variant in North America (PMID: 19176896, 18055113, 9029070), therefore, the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant is also referred to as A4V in published literature. This variant occurs as the most likely explanation for disease in a significant number of cases, suggesting this variant is associated with disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 20184893, 19635794, 16945901, 23291526) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2021	PS3, PS4, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	Functional studies demonstrate a 50% reduction in activity of cytosolic SOD1 in patients with A5V compared to unaffected individuals (Rosen et al., 1994; Lindberg et al., 2002); Additional published functional studies demonstrate that the variant alters protein stability and activity, results in reduced nuclear localization, and leads to formation of inclusions (Brasil et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28884318, 8351519, 19618436, 31781168, 29564924, 31134679, 19176896, 26362407, 26298469, 26084641, 12482932, 21257910, 16945901, 20404910, 23118898, 23784844, 21930207, 22094223, 18319614, 24793051, 20184893, 21549128, 20399791, 23291526, 25096579, 23760509, 20404329, 19635794, 19196430, 24134191, 7951249, 19483195, 22589106, 19259395, 19751676, 23280792, 19800308, 26413785) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2014	- -

SOD1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2023

The SOD1 c.14C>T variant is predicted to result in the amino acid substitution p.Ala5Val. This variant, previously described as p.Ala4Val using legacy nomenclature, has been repeatedly reported to be causative for amyotrophic lateral sclerosis (Deng et al. 1993. PubMed ID: 8351519; Saeed et al. 2009. PubMed ID: 19176896). The c.14C>T variant has also been interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14763/). We interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Pathogenic	0.99	D;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	0.069	A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;N
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;T
Sift4G	Uncertain	0.014	D;T
Polyphen		1.0	D;.
Vest4		0.65
MutPred		0.94		Gain of methylation at K4 (P = 0.0344);Gain of methylation at K4 (P = 0.0344);
MVP		0.98
MPC		1.9
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs121912442; hg19: chr21-33032096;