Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV000193991 | SCV000246672 | pathogenic | Menkes kinky-hair syndrome | 2013-02-08 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001857689 | SCV002240383 | pathogenic | Menkes kinky-hair syndrome; Cutis laxa, X-linked; X-linked distal spinal muscular atrophy type 3 | 2022-08-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ATP7A function (PMID: 18752978, 28389643). 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) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7A protein function. ClinVar contains an entry for this variant (Variation ID: 210418). This missense change has been observed in individual(s) with ATP7A-related copper transport disorders (PMID: 18752978, 28389643, 28397151). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 727 of the ATP7A protein (p.Gly727Arg). |
| Ambry Genetics | RCV002517916 | SCV003727463 | pathogenic | Inborn genetic diseases | 2021-04-01 | criteria provided, single submitter | clinical testing | The c.2179G>A (p.G727R) alteration is located in exon 10 (coding exon 9) of the ATP7A gene. This alteration results from a G to A substitution at nucleotide position 2179, causing the glycine (G) at amino acid position 727 to be replaced by an arginine (R). This mutation was identified in three males with Menkes disease (Tang, 2008). This mutation was also observed in a female with severe intellectual disability, short fine hair, a large fontanelle, hypotonia, dry skin with hypopigmentation, increased copper uptake and retention in fibroblasts, and a family history of a severely affected brother; she had a normal karyotype and skewed X inactivation (Møller, 2012). Internal structural analysis indicates that this alteration is more disruptive than a general cutoff for pathogenic variants (Gourdon, 2011). Western blot and RT-PCR analysis from patient fibroblasts demonstrated normal transcript levels, decreased protein levels, and increased protein degradation compared to wild type (Tang, 2008) Based on the available evidence, this alteration is classified as pathogenic. |
| Gene |
RCV003227709 | SCV003924629 | pathogenic | not provided | 2023-05-10 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a damaging effect with protein instability and degradation, and hampered copper-induced trafficking (Tang et al., 2008; Skjrringe et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28397151, 30618512, 26582918, 24882692, 7977350, 21208200, 28389643, 22264391, 20652413, 25428120, 18752978, 27535533, 34430447, 33894639, 34390520) |
| Inherited Neuropathy Consortium Ii, |
RCV000193991 | SCV004012032 | uncertain significance | Menkes kinky-hair syndrome | 2016-01-06 | no assertion criteria provided | literature only |