ClinVar Miner

Submissions for variant NM_000052.7(ATP7A):c.278C>T (p.Thr93Met) (rs539177302)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414022 SCV000491101 uncertain significance not specified 2016-12-15 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ATP7A gene. The T93M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and it was not observed with any significant frequency in the 1000 Genomes Project and Exome Aggregation Consortium, indicating it is not a common benign variant in these populations. The T93M 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. However, this substitution occurs at a position that is not conserved across species and in silico analysis predicts this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000530559 SCV000639978 uncertain significance Menkes kinky-hair syndrome; Cutis laxa, X-linked; Distal spinal muscular atrophy, X-linked 3 2019-09-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 93 of the ATP7A protein (p.Thr93Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs539177302, ExAC 0.01%). This variant has not been reported in the literature in individuals with an ATP7A-related disease. ClinVar contains an entry for this variant (Variation ID: 372700). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on ATP7A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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