Submissions for variant NM_000702.4(ATP1A2):c.194G>T (p.Arg65Leu)

gnomAD frequency: 0.00019  dbSNP: rs187733403

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723890	SCV000230127	uncertain significance	not provided	2015-04-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000723890	SCV000240353	uncertain significance	not provided	2016-05-20	criteria provided, single submitter	clinical testing	The R65L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The 1000 Genomes Project reports R65L was observed in 4/1008 (0.4%) alleles from individuals of East Asian background. The R65L 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 that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Illumina Laboratory Services, Illumina	RCV000333542	SCV000349870	benign	Alternating hemiplegia of childhood 1	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	RCV001093780	SCV000349871	benign	Migraine, familial hemiplegic, 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.
Invitae	RCV000382532	SCV000756609	benign	Familial hemiplegic migraine	2023-12-02	criteria provided, single submitter	clinical testing
Department of Neurology, Xijing Hospital, Fourth Military Medical University	RCV002295287	SCV002553228	uncertain significance	Developmental and epileptic encephalopathy 98	2022-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415763	SCV002719359	benign	Inborn genetic diseases	2019-04-05	criteria provided, single submitter	clinical testing	This alteration is classified as 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.