Submissions for variant NM_000702.4(ATP1A2):c.736A>G (p.Asn246Asp)

gnomAD frequency: 0.00002  dbSNP: rs764917849

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519514	SCV000621990	uncertain significance	not provided	2017-10-30	criteria provided, single submitter	clinical testing	The N246D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N246D variant is observed in 1/15288 (0.007%) alleles from individuals of African background (Lek et al., 2016). The N246D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, Asparagine is observed at this position in evolution. In silico analysis predicts this variant is probably 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.
Ambry Genetics	RCV002314919	SCV000848123	uncertain significance	Inborn genetic diseases	2021-04-28	criteria provided, single submitter	clinical testing	The c.736A>G (p.N246D) alteration is located in exon 7 (coding exon 7) of the ATP1A2 gene. This alteration results from a A to G substitution at nucleotide position 736, causing the asparagine (N) at amino acid position 246 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Centogene AG - the Rare Disease Company	RCV001809475	SCV002059237	uncertain significance	Migraine, familial hemiplegic, 2	2020-08-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000717274	SCV002191273	uncertain significance	Familial hemiplegic migraine	2023-07-25	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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ATP1A2 protein function. ClinVar contains an entry for this variant (Variation ID: 453128). This variant has not been reported in the literature in individuals affected with ATP1A2-related conditions. This variant is present in population databases (rs764917849, gnomAD 0.007%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 246 of the ATP1A2 protein (p.Asn246Asp).
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV001809475	SCV005442298	uncertain significance	Migraine, familial hemiplegic, 2	2024-12-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409755	SCV004114589	uncertain significance	ATP1A2-related disorder	2023-12-11	no assertion criteria provided	clinical testing	The ATP1A2 c.736A>G variant is predicted to result in the amino acid substitution p.Asn246Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.