Submissions for variant NM_003664.5(AP3B1):c.1022G>A (p.Arg341His)

gnomAD frequency: 0.00023  dbSNP: rs141832130

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640580	SCV000762174	uncertain significance	Hermansky-Pudlak syndrome 2	2022-08-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 341 of the AP3B1 protein (p.Arg341His). This variant is present in population databases (rs141832130, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with AP3B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 533468). 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"). 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000640580	SCV001468409	uncertain significance	Hermansky-Pudlak syndrome 2	2021-03-30	criteria provided, single submitter	clinical testing	AP3B1 NM_003664.4 exon 9 p.Arg341His (c.1022G>A): This variant has not been reported in the literature but is present in 0.03% (49/129098) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-77473181-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:533468). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Mayo Clinic Laboratories, Mayo Clinic	RCV001729668	SCV002542124	uncertain significance	not provided	2021-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782487	SCV005394320	uncertain significance	not specified	2024-09-16	criteria provided, single submitter	clinical testing	Variant summary: AP3B1 c.1022G>A (p.Arg341His) 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 0.00022 in 251320 control chromosomes, predominantly at a frequency of 0.0004 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome (0.00022 vs 0.0005), allowing no conclusion about variant significance. c.1022G>A has been reported in the literature in one individual affected with NK/T-cell lymphoma of nasal type (example, Guan_2021). 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 publication has been ascertained in the context of this evaluation (PMID: 34170459). ClinVar contains an entry for this variant (Variation ID: 533468). Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Genetics, Academic Medical Center	RCV001729668	SCV001979144	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729668	SCV001980141	uncertain significance	not provided		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000640580	SCV002525464	uncertain significance	Hermansky-Pudlak syndrome 2		no assertion criteria provided	research