ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.1474G>A (p.Glu492Lys) (rs142348542)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727278 SCV000240359 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing The E492K missense variant has been reported previously in a five-year-old male with hemiplegic migraine and his mother who had a history of migraines with aura but no hemiplegic attacks, and in vitro functional studies suggest it results in partial loss of function due to reduced cell survival when transfected into HeLa cells (de Vries et al., 2007). The E492K variant is observed in 42/65664 (0.06%) of alleles from individuals of European background in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016). This variant is a non-conservative amino acid substitution that occurs at a position that is conserved in mammals; however, Lysine is observed at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the E492K 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 Clinical Services Laboratory,Illumina RCV000265061 SCV000349892 likely benign Alternating hemiplegia of childhood 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000324860 SCV000349893 likely benign Familial hemiplegic migraine 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000324860 SCV000632361 uncertain significance Familial hemiplegic migraine 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 492 of the ATP1A2 protein (p.Glu492Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs142348542, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with hemiplegic migraine and his mother affected with migraines without hemiplegic attacks (PMID: 18056581). ClinVar contains an entry for this variant (Variation ID: 204888). Experimental studies have shown that this missense change results in partial loss of function in cell culture (PMID: 18056581). 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727278 SCV000707185 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing

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