Submissions for variant NM_001940.4(ATN1):c.1464GCA[8] (p.Gln496_Gln502del)

dbSNP: rs60216939

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174597	SCV001337790	uncertain significance	not specified	2020-01-20	criteria provided, single submitter	clinical testing	Variant summary: ATN1 c.1488_1508del21 (p.Gln496_Gln502del) results in an in-frame deletion that is predicted to remove seven amino acids from the encoded protein. The variant was absent in 247226 control chromosomes, however the variant is located in a highly variable region, with many del/dups present in gnomad. Dentatorubral-pallidoluysian atrophy (DRPLA) results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the ATN1 gene (Genetics Home Reference Page), whereas other types of mutations may be related to other ATN1-related disorders. c.1488_1508del21 has been reported in the literature in at least one individual for which whole exome sequencing detected causitive mutations other than the variant of interest (Chia_2018). This report does not provide unequivocal conclusions about association of the variant with DRPLA or other ATN1-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as a VUS.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355035	SCV001549795	likely benign	not provided		no assertion criteria provided	clinical testing	The ATN1 p.Gln496_Gln502del variant was not identified in the dbSNP or LOVD 3.0 databases, however it was identified in the Clinvar and Cosmic databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant was identified in the homozygous form in two children from a consanguineous family presenting with severe, global developmental delay, however the cause of their developmental delay was attributed to biallelic variants in CAMK2A (Chia_2018_PMID: 29784083). This variant is an in-frame deletion resulting in the removal of 7 glutamine (gln) residues at codon 496, within a glutamine repeat region. The insertion of (CAG)n or glutamine repeats has been found to cause dentatorubro-pallidoluysian atrophy, however this variant is a (CAG)n repeat deletion within the normal range considered of 6-35 repeats (Koide_1994_PMID: 8136840; MIM: 607462). The impact of this alteration on ATN1 protein function is not known, however MutationTaster predicts this variant to be a polymorphism. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.