rs121912442

Variant summary

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

The NM_000454(SOD1):c.14C>T(p.Ala5Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes 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. A5S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SOD1
NM_000454 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 5.94

Links

SOD1 (HGNC:11179):

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_000454

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 linkuse as main transcript	c.14C>T	p.Ala5Val	missense_variant	1/5	ENST00000270142.11

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000359

AC:

AN:

250494

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135690

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:

0.0000796

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000318

AC:

AN:

628436

Hom.:

AF XY:

0.00

AC XY:

AN XY:

342390

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000571

Gnomad4 OTH exome

AF:

0.00

Alfa

AF:

0.0000308

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

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	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2021	PS3, PS4, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics Inc	Oct 23, 2020	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. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant causes an increase in unfolded monomers and disruption of the dimer interface elements (PMID: 20184893, 19635794, 16945901, 23291526). Based on internal data, this variant occurs with an alternate explanation for disease significantly less often than expected, suggesting this variant may be associated with disease. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2014	- -

Amyotrophic lateral sclerosis type 1

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	May 12, 2009	- -
not provided, no assertion 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 02, 2022	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. 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	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.42

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.80

LIST_S2

Pathogenic

0.99

D;T

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

0.069

A;A

PrimateAI

Uncertain

0.67

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

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.79

gMVP

0.89

Splicing

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

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over