Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001880204 | SCV002112023 | uncertain significance | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 455 of the AP3D1 protein (p.Ala455Thr). This variant is present in population databases (rs200459002, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with AP3D1-related conditions. ClinVar contains an entry for this variant (Variation ID: 988866). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Fulgent Genetics, |
RCV002493462 | SCV002788456 | uncertain significance | Hermansky-Pudlak syndrome 10 | 2021-11-04 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331095 | SCV004038801 | uncertain significance | not specified | 2023-08-22 | criteria provided, single submitter | clinical testing | Variant summary: AP3D1 c.1363G>A (p.Ala455Thr) results in a non-conservative amino acid change located in the Clathrin/coatomer adaptor, adaptin-like, N-terminal domain (IPR002553) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 278336 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 5.022 fold of the estimated maximal expected allele frequency for a pathogenic variant in AP3D1 causing Hermansky-Pudlak Syndrome phenotype (0.00016), suggesting that the variant may be benign. c.1363G>A has been reported in the literature in individuals affected with platelet dysfunction (e.g., Almanzi_2020, Louzil_2022), however, these report(s) do not provide unequivocal conclusions about association of the variant with Hermansky-Pudlak Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32935436, 36430862). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. |
| Birmingham Platelet Group; University of Birmingham | RCV001270585 | SCV001450884 | uncertain significance | Abnormal bleeding; Thrombocytopenia | 2020-05-01 | no assertion criteria provided | research |