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.
Verdict is Pathogenic. Variant got 16 ACMG points.
|SOD1||ENST00000389995.4 ||c.14C>T||p.Ala5Val||missense_variant, splice_region_variant||1/5||3|
GnomAD3 genomesCov.: 33 GnomAD3 exomes AF: 0.0000359AC: 9AN: 250494Hom.: 0 AF XY: 0.0000295AC XY: 4AN XY: 135690 GnomAD4 exome AF: 0.00000318AC: 2AN: 628436Hom.: 0 AF XY: 0.00AC XY: 0AN XY: 342390
Submissions by phenotype
|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, 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||- -|
Find out detailed SpliceAI scores and Pangolin per-transcript scores at