ClinVar Miner

Submissions for variant NM_000702.4(ATP1A2):c.193C>T (p.Arg65Trp) (rs121918619)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442150 SCV000518163 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing The R65W variant in the ATP1A2 gene has been reported previously in three siblings with familial hemiplegic migraine (FHM), and was not present in another sibling who suffered from typical migraines without aura (Tonelli et al., 2007). The R65W variant is observed in 14/126278 (0.01%) alleles from individuals of European background (Lek et al., 2016). The R65W 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. 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 RCV001097809 SCV001254124 benign Alternating hemiplegia of childhood 1 2017-08-31 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000013792 SCV001254125 uncertain significance Familial hemiplegic migraine type 2 2017-08-31 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197306 SCV001367969 uncertain significance Autistic behavior; Mandibular prognathia; Delayed speech and language development; Small earlobe; Intellectual disability; Prominent glabella; Attention deficit hyperactivity disorder 2019-05-13 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
Invitae RCV001221618 SCV001393674 uncertain significance Familial hemiplegic migraine 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 65 of the ATP1A2 protein (p.Arg65Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121918619, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed to segregate with hemiplegic migraine in a family (PMID: 17877748). ClinVar contains an entry for this variant (Variation ID: 12929). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
OMIM RCV000013792 SCV000034039 pathogenic Familial hemiplegic migraine type 2 2007-12-01 no assertion criteria provided literature only

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