Submissions for variant NM_152296.5(ATP1A3):c.410_412del (p.Ser137del)

dbSNP: rs1555865385

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599115	SCV000709988	likely pathogenic	not provided	2018-01-25	criteria provided, single submitter	clinical testing	The c.410_412delCCT variant in the ATP1A3 gene has been reported previously to segregate in a family with dystonia, with one unaffected family member also reported to harbor the c.410_412delCCT variant suggesting reduced penetrance for this variant (Wilcox et al., 2014). This variant causes an in-frame deletion of codon Serine 137, denoted p.Ser137del. The c.410_412delCCT variant is not observed in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret c.410_412delCCT as a likely pathogenic variant.
Invitae	RCV000644926	SCV000766648	uncertain significance	Dystonia 12	2017-11-09	criteria provided, single submitter	clinical testing	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 for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been reported to segregate with disease in a single family affected with dystonia (PMID: 25359261). This variant is also referred to as c.443_445del (p.Ser148del) in the literature. This variant is not present in population databases (ExAC no frequency). This variant, c.410_412delCCT, results in the deletion of 1 amino acid(s) of the ATP1A3 protein (p.Ser137del), but otherwise preserves the integrity of the reading frame.
Molecular Genetics, Royal Melbourne Hospital	RCV001823004	SCV002072636	likely pathogenic	ATP1A3-associated neurological disorder	2021-11-11	criteria provided, single submitter	clinical testing	This sequence change is predicted to cause a change in the length of the protein due to an in-frame deletion of one amino acid in a non-repeat region of the ATP1A3 protein (p.(Ser137del)). The region deleted is highly conserved (100 vertebrates, UCSC), and is located in a transmembrane helical region. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with dystonia-parkinsonism, and has been reported to segregate with disease in eight affected family members from a single family (Royal Melbourne Hospital; PMID: 25359261, described as c.443_445delGAG, p.Ser148del). It has been classified as a variant of uncertain significance and likely pathogenic (ClinVar ID: 503717). Furthermore, two missense variants at the same position (p.Ser137Phe and p.Ser137Tyr) have been identified in cases with alternating hemiplegia of childhood (PMID: 22842232). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Supporting, PM2_Supporting, PM4_Supporting.