Submissions for variant NM_015046.7(SETX):c.4865C>T (p.Pro1622Leu)

gnomAD frequency: 0.00005  dbSNP: rs140781535

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518382	SCV000615192	uncertain significance	not specified	2017-04-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764811	SCV000895957	uncertain significance	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000764811	SCV002306806	benign	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2022-12-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002341213	SCV002639406	uncertain significance	Inborn genetic diseases	2022-05-03	criteria provided, single submitter	clinical testing	The p.P1622L variant (also known as c.4865C>T), located in coding exon 8 of the SETX gene, results from a C to T substitution at nucleotide position 4865. The proline at codon 1622 is replaced by leucine, an amino acid with similar properties. This alteration was reported in one patient with sporadic amyotrophic lateral sclerosis (ALS) with onset in his 40's (Cady J et al. Ann Neurol, 2015 Jan;77:100-13).This amino acid position is not well conserved in available vertebrate species, and leucine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of autosomal dominant juvenile amyotrophic lateral sclerosis 4 (ALS4); however, its contribution to the development of autosomal recessive spinocerebellar ataxia with axonal neuropathy 2 (SCAN2) is uncertain.
Genome-Nilou Lab	RCV003233685	SCV003931356	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003233686	SCV003931357	uncertain significance	Amyotrophic lateral sclerosis type 4	2023-02-08	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003233686	SCV004812669	uncertain significance	Amyotrophic lateral sclerosis type 4	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change in SETX is predicted to replace proline with leucine at codon 1622, p.(Pro1622Leu). The proline residue is weakly conserved (100 vertebrates, UCSC), and is not located in an annotated domain. There is a moderate physicochemical difference between proline and leucine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.03% (6/19,954 alleles) in the East Asian population. This variant has been reported in at least one individual with amyotrophic lateral sclerosis (PMID: 25382069), and has been reported as likely benign and as a variant of uncertain significance (ClinVar ID: 448330). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.231). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000518382	SCV005394464	uncertain significance	not specified	2024-09-13	criteria provided, single submitter	clinical testing	Variant summary: SETX c.4865C>T (p.Pro1622Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251422 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in SETX causing Amyotrophic Lateral Sclerosis Type 4, allowing no conclusion about variant significance. c.4865C>T has been reported in the literature (Kars_2021, Cady_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25382069, 34426522). ClinVar contains an entry for this variant (Variation ID: 448330). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579382	SCV001807024	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579382	SCV001928792	likely benign	not provided		no assertion criteria provided	clinical testing