Submissions for variant NM_020919.4(ALS2):c.1641G>A (p.Arg547=)

gnomAD frequency: 0.00038  dbSNP: rs34122078

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557506	SCV000640083	uncertain significance	Infantile-onset ascending hereditary spastic paralysis	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 547 of the ALS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ALS2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs34122078, gnomAD 0.07%). 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: 465181). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Illumina Laboratory Services, Illumina	RCV001141937	SCV001302324	uncertain significance	Amyotrophic lateral sclerosis type 2, juvenile	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001141938	SCV001302325	uncertain significance	ALS2-related disorder	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001553526	SCV001774411	uncertain significance	not provided	2020-12-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
Ambry Genetics	RCV003243183	SCV003964285	likely benign	Inborn genetic diseases	2023-06-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001553526	SCV001927185	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001553526	SCV001968665	likely benign	not provided		no assertion criteria provided	clinical testing