ClinVar Miner

Submissions for variant NM_000052.7(ATP7A):c.1597A>G (p.Asn533Asp) (rs1057524455)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000422781 SCV000535616 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing The c.1597 A>G (N533D) variant of uncertain significance in the ATP7A gene 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, or in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variant in these populations. At the nucleotide level, c.1597 A>G (N533D) occurs at an exon position that may affect splicing. Two in silico splicing algorithms predict that c.1597 A>G (N533D) creates a cryptic splice donor site upstream of the natural splice donor site in intron 6 of the ATP7A gene. However, in the absence of functional mRNA studies, the physiological consequence of this variant on splicing cannot be precisely determined. At the protein level, the c.1597 A>G (N533D) variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is conserved in mammals, although D533 is the native residue in at least one species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no pathogenic missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.Therefore, based on the currently available information, it is unclear whether this X-linked variant is pathogenic or rare benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000640896 SCV000762500 uncertain significance Menkes kinky-hair syndrome; Cutis laxa, X-linked; Distal spinal muscular atrophy, X-linked 3 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 533 of the ATP7A protein (p.Asn533Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ATP7A-related disease. ClinVar contains an entry for this variant (Variation ID: 392357). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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