Submissions for variant NM_020919.4(ALS2):c.2241C>T (p.Tyr747=)

gnomAD frequency: 0.00208  dbSNP: rs3219160

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082502	SCV000290503	benign	Infantile-onset ascending hereditary spastic paralysis	2025-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000388670	SCV000426317	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	RCV000294407	SCV000426318	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756988	SCV000885000	likely benign	not provided	2017-07-14	criteria provided, single submitter	clinical testing	The c.2241C>T variant (rs3219160) does not alter the amino acid sequence of the ALS2 protein and computational splice site prediction algorithms do not predict a change in the nearest splice site or creation of a cryptic splice site. This variant has not been reported in association with ALS in medical literature or in gene specific variation databases. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.18 percent (identified on 503 out of 276,712 chromosomes including 2 homozygotes). Based on these observations, the c.2241C>T variant is likely to be benign.
GeneDx	RCV000756988	SCV001769839	likely benign	not provided	2020-07-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001848004	SCV002104706	likely benign	Hereditary spastic paraplegia	2020-03-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000756988	SCV004033852	likely benign	not provided	2025-01-01	criteria provided, single submitter	clinical testing	ALS2: BP4, BS2
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000756988	SCV001808665	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000756988	SCV001969975	likely benign	not provided		no assertion criteria provided	clinical testing