Submissions for variant NM_000454.5(SOD1):c.14C>T (p.Ala5Val)

gnomAD frequency: 0.00004  dbSNP: rs121912442

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000518025	SCV000224225	pathogenic	not provided	2014-07-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000518025	SCV000615369	pathogenic	not provided	2023-06-29	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000015885	SCV000644790	pathogenic	Amyotrophic lateral sclerosis type 1	2025-01-17	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Fulgent Genetics, Fulgent Genetics	RCV000015885	SCV000893547	pathogenic	Amyotrophic lateral sclerosis type 1	2018-10-31	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000518025	SCV001715588	pathogenic	not provided	2023-07-17	criteria provided, single submitter	clinical testing	PP3, PM2_moderate, PS3, PS4_moderate
GeneDx	RCV000518025	SCV001767218	pathogenic	not provided	2020-02-18	criteria provided, single submitter	clinical testing	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)
Neuberg Centre For Genomic Medicine, NCGM	RCV000015885	SCV004048541	pathogenic	Amyotrophic lateral sclerosis type 1		criteria provided, single submitter	clinical testing	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.
OMIM	RCV000015885	SCV000036152	pathogenic	Amyotrophic lateral sclerosis type 1	2009-05-12	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000015885	SCV001423357	not provided	Amyotrophic lateral sclerosis type 1		no assertion provided	phenotyping only	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.
PreventionGenetics, part of Exact Sciences	RCV003390686	SCV004112622	pathogenic	SOD1-related disorder	2024-08-27	no assertion criteria provided	clinical testing	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/) and is reported in 0.0080% of alleles in individuals of European (Non-Finnish) descent in gnomAD. We interpret this variant as pathogenic.