Submissions for variant NM_015046.7(SETX):c.7157T>C (p.Ile2386Thr)

dbSNP: rs201887051

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000992957	SCV001145574	uncertain significance	not provided	2019-08-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282419	SCV002571971	uncertain significance	not specified	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: SETX c.7157T>C (p.Ile2386Thr) results in a non-conservative amino acid change located in the DNA2/NAM7 helicase-like, C-terminal domain (IPR041679) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7157T>C has been reported in the literature in an individual with a diagnosis for Ataxia with oculomotor apraxia type 2 (example: Anheim_2009). This report does 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV003233907	SCV003931855	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003233908	SCV003931866	uncertain significance	Amyotrophic lateral sclerosis type 4	2023-02-08	criteria provided, single submitter	clinical testing
Invitae	RCV003769318	SCV004579155	uncertain significance	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-09-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 805434). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2386 of the SETX protein (p.Ile2386Thr). This variant is present in population databases (rs201887051, gnomAD 0.0009%). This missense change has been observed in individual(s) with ataxia with oculomotor apraxia type 2 (PMID: 19696032). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SETX protein function. 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.