Submissions for variant NM_015046.7(SETX):c.5308_5311del (p.Glu1770fs)

dbSNP: rs750959420

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516701	SCV000615196	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and appears to be associated with disease in at least one family. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000850075	SCV000992240	pathogenic	Cerebellar ataxia	2018-08-06	criteria provided, single submitter	clinical testing
UM ALS/MND Lab, University Of Malta	RCV001260555	SCV001426210	likely pathogenic	Amyotrophic lateral sclerosis	2020-07-31	criteria provided, single submitter	case-control	Allele frequency for the Glu1770Ilefs*15 variant in SETX was 0.000075 in ALS cases and 0 in controls within the Project MinE ALS case-control cohort, which favors evidence supporting our criteria to be classified as likely pathogenic
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814179	SCV001755541	pathogenic	Abnormal central motor function	2021-07-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527525	SCV003015658	pathogenic	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu1770Ilefs*15) in the SETX gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETX are known to be pathogenic (PMID: 14770181). This variant is present in population databases (rs750959420, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with autosomal recessive cerebellar ataxia (PMID: 18405395). ClinVar contains an entry for this variant (Variation ID: 448333). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000516701	SCV003825568	pathogenic	not provided	2022-03-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000516701	SCV003929762	pathogenic	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31656689, 31493945, 18405395, 33624863, 29858556, 19696032, 30560021, 27528516)
Genome-Nilou Lab	RCV000664235	SCV003931336	likely pathogenic	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-02-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Cologne University	RCV000664235	SCV000787802	pathogenic	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2018-04-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732921	SCV005365649	pathogenic	SETX-related disorder	2024-03-04	no assertion criteria provided	clinical testing	The SETX c.5308_5311delGAGA variant is predicted to result in a frameshift and premature protein termination (p.Glu1770Ilefs*15). This variant was reported in the homozygous state in multiple individuals with autosomal recessive spinocerebellar ataxia and was found to segregate with disorder in at least two unrelated families (Nicolaou et al. 2008. PubMed ID: 18405395; Algahtani et al. 2018. PubMed ID: 30560021; Table S1, Vural et al. 2021. PubMed ID: 33624863). This variant was also documented along with a canonical splice variant in an individual with autosomal recessive spinocerebellar ataxia (Marelliet al. 2016. PubMed ID: 27528516). None of the heterozygous carriers of this variant were reported to be symptomatic. This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in SETX are expected to be pathogenic. This variant is interpreted as pathogenic.