Submissions for variant NM_152296.5(ATP1A3):c.2767G>A (p.Asp923Asn)

dbSNP: rs267606670

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000128465	SCV000246634	pathogenic	Alternating hemiplegia of childhood 2	2015-07-23	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000128465	SCV000746607	pathogenic	Alternating hemiplegia of childhood 2	2017-10-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763432	SCV000894198	pathogenic	Cerebellar ataxia-areflexia-pes cavus-optic atrophy-sensorineural hearing loss syndrome; Dystonia 12; Alternating hemiplegia of childhood 2	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000013778	SCV001149690	pathogenic	Dystonia 12	2019-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013778	SCV001230208	pathogenic	Dystonia 12	2023-09-08	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 923 of the ATP1A3 protein (p.Asp923Asn). This missense change has been observed in individual(s) with ATP1A3-related conditions (PMID: 19652145, 22924536, 23483595, 28849312). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12915). 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) performed at Invitae indicates that this missense variant is expected to disrupt ATP1A3 protein function. Experimental studies have shown that this missense change affects ATP1A3 function (PMID: 20576601). This variant disrupts the p.Asp923 amino acid residue in ATP1A3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22850527, 24842602). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000128465	SCV002059005	pathogenic	Alternating hemiplegia of childhood 2	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000012915, PS1_S). Ithas been previously reported as de novo in a similarly affected individual (PMID: 24842602, PS2_S). The variant was co-segregated with Alternating hemiplegia of childhood 2 in multiple affected family members (PMID: 23483595, PP1_P). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 19652145, 22924536, 23483595, 28849312, 24842602, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20576601, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.784, 3CNET: 0.979, PP3_P). A missense variant is a common mechanism associated with Alternating hemiplegia of childhood 2 (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000161148, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000013778	SCV002567894	pathogenic	Dystonia 12	2022-08-25	criteria provided, single submitter	clinical testing	variant is absent in gnomAD and in-house DB; many publications describe cases and performed functional analyses to grade as pathogenic
GeneDx	RCV003233069	SCV003930892	pathogenic	not provided	2023-06-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Einholm et al., 2010; Lazarov et al., 2020); Missense variants in nearby residues reported in the Human Gene Mutation Database (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19652145, 33144327, 28849312, 31737037, 18675996, 22924536, 23483595, 24123283, 31425744, 31361359, 24842602, 22850527, 20576601, 32653672, 23527305, 34042254, 33098801, 35872528)
Illumina Laboratory Services, Illumina	RCV003389231	SCV004101307	pathogenic	ATP1A3-associated neurological disorder	2023-08-10	criteria provided, single submitter	clinical testing	The ATP1A3 c.2767G>A (p.Asp923Asn) missense variant has been identified in individuals with ATP1A3-related neurologic disorders, including in a de novo state (PMID:18675996; 22924536; 23483595; 31361359; 31737037). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Three other missense changes at the same residue have been reported to be clinically significant in ClinVar. Functional evidence demonstrated that this variant impacts protein function (PMID: 20576601). This variant was identified in a de novo state. Based on the available evidence, the c.2767G>A (p.Asp923Asn) variant is classified as pathogenic for ATP1A3-associated neurological disorder.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV004577942	SCV005061784	pathogenic	Seizure	2024-06-19	criteria provided, single submitter	clinical testing
OMIM	RCV000013778	SCV000034025	pathogenic	Dystonia 12	2014-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000013778	SCV000087047	not provided	Dystonia 12		no assertion provided	literature only
OMIM	RCV000128465	SCV000172167	pathogenic	Alternating hemiplegia of childhood 2	2014-01-01	no assertion criteria provided	literature only