Submissions for variant NM_020919.4(ALS2):c.4957C>T (p.Arg1653Cys)

gnomAD frequency: 0.00011  dbSNP: rs200416249

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001141602	SCV001301961	uncertain significance	ALS2-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001141603	SCV001301962	uncertain significance	Amyotrophic lateral sclerosis type 2, juvenile	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208992	SCV001380410	uncertain significance	Infantile-onset ascending hereditary spastic paralysis	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1653 of the ALS2 protein (p.Arg1653Cys). This variant is present in population databases (rs200416249, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ALS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 898013). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV002509617	SCV002818842	uncertain significance	not provided	2023-01-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as a variant of uncertain significance in an individual with a diagnosis of juvenile primary lateral sclerosis (Alves De Siqueira Carvalho et al., 2022); This variant is associated with the following publications: (PMID: 34738851)
CeGaT Center for Human Genetics Tuebingen	RCV002509617	SCV005050918	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ALS2: PM2:Supporting, BP4