Submissions for variant NM_015046.7(SETX):c.7406T>C (p.Leu2469Pro)

gnomAD frequency: 0.00005  dbSNP: rs151304085

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000361458	SCV000477789	uncertain significance	Amyotrophic lateral sclerosis type 4	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	RCV000266732	SCV000477790	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	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.
Ambry Genetics	RCV002379256	SCV002671241	uncertain significance	Inborn genetic diseases	2023-06-23	criteria provided, single submitter	clinical testing	The c.7406T>C (p.L2469P) alteration is located in exon 26 (coding exon 24) of the SETX gene. This alteration results from a T to C substitution at nucleotide position 7406, causing the leucine (L) at amino acid position 2469 to be replaced by a proline (P). The alteration has been observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.7406T>C alteration was observed in 0.0021% (6/282816) of total alleles studied, with a frequency of 0.0046% (6/129160) in the European (non-Finnish) subpopulation. This amino acid position is conserved in mammals. The alteration is predicted benign by in silico models:_x000D_ _x000D_ The p.L2469P alteration is predicted to be benign by Polyphen and tolerated by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002524586	SCV003249867	likely benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2022-12-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV004546488	SCV005042442	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SETX: PM2:Supporting