Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000623523 | SCV000740969 | likely pathogenic | Inborn genetic diseases | 2015-06-15 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002531883 | SCV003291240 | uncertain significance | Hereditary spastic paraplegia 47 | 2022-06-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 206 of the AP4B1 protein (p.Arg206Gln). This variant also falls at the last nucleotide of exon 5, which is part of the consensus splice site for this exon. This variant is present in population databases (rs149705131, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary spastic paraplegia (PMID: 31915823, 32979048). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 520727). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Neuberg Centre For Genomic Medicine, |
RCV002531883 | SCV004176424 | likely pathogenic | Hereditary spastic paraplegia 47 | 2023-07-22 | criteria provided, single submitter | clinical testing | The missense/ splice region variant c.617G>Ap.Arg206Gln in AP4B1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with hereditary spastic paraplegia Ebrahimi-Fakhari et al., 2020. This variant is reported with the allele frequency of 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid Arg at position 206 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen-probably damaging, SIFT-damaging and Mutation Taster-disease causing predict a damaging effect on protein structure and function for this variant.This variant is predicted as damaging by SpliceAI Prediction. The reference amino acid p.Arg206Gln in AP4B1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates .It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Likely Pathogenic. |
| Gene |
RCV004719904 | SCV005325853 | pathogenic | not provided | 2023-11-15 | criteria provided, single submitter | clinical testing | Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25693842, 21620353, 23472171, 24700674, 26795593, 19559397, 23167973, 20972249, 29193663, 22290197, 24395635, 25552650, 31915823, 32979048) |
| Yale Center for Mendelian Genomics, |
RCV001849410 | SCV002106840 | likely pathogenic | Spastic paraplegia | 2020-10-01 | no assertion criteria provided | literature only |