Submissions for variant NM_015046.7(SETX):c.3057TGA[4] (p.Asp1023_Asp1024del)

dbSNP: rs572772837

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000644820	SCV000766535	uncertain significance	Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-06-29	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with SETX-related conditions. 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 536381). This variant is present in population databases (rs760025407, gnomAD 0.01%). This variant, c.3069_3074del, results in the deletion of 2 amino acid(s) of the SETX protein (p.Asp1023_Asp1024del), but otherwise preserves the integrity of the reading frame.
GeneDx	RCV002286770	SCV002577316	uncertain significance	not provided	2022-03-28	criteria provided, single submitter	clinical testing	In-frame deletion of 2 amino acids in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002449037	SCV002753008	likely benign	Inborn genetic diseases	2023-02-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV003233773	SCV003931467	uncertain significance	Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2	2023-02-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003233774	SCV003931468	uncertain significance	Amyotrophic lateral sclerosis type 4	2023-02-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330860	SCV004037904	uncertain significance	not specified	2023-08-04	criteria provided, single submitter	clinical testing	Variant summary: SETX c.3069_3074delTGATGA (p.Asp1023_Asp1024del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 2.4e-05 in 250820 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3069_3074delTGATGA in individuals affected with Amyotrophic Lateral Sclerosis Type 4 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.