Submissions for variant NM_152296.5(ATP1A3):c.1387C>T (p.Arg463Cys)

gnomAD frequency: 0.00050  dbSNP: rs150785666

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441666	SCV000512197	uncertain significance	not specified	2016-12-05	criteria provided, single submitter	clinical testing	The R463C variant in the ATP1A3 gene has not been previously reported as a pathogenic or benign variant to our knowledge. The R463C variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R463C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function.
Invitae	RCV000547051	SCV000645393	likely benign	Dystonia 12	2024-01-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000547051	SCV001290693	benign	Dystonia 12	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV001131091	SCV001290694	benign	Alternating hemiplegia of childhood 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000547051	SCV001366154	uncertain significance	Dystonia 12	2019-03-06	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3.
Ambry Genetics	RCV002524753	SCV003567564	likely benign	Inborn genetic diseases	2022-08-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
CeGaT Center for Human Genetics Tuebingen	RCV001777161	SCV004143855	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ATP1A3: PP2, BS2
PreventionGenetics, part of Exact Sciences	RCV003970106	SCV004785454	likely benign	ATP1A3-related condition	2020-08-25	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
OMIM	RCV001777161	SCV002014597	uncertain significance	not provided	2021-11-10	no assertion criteria provided	literature only