Submissions for variant NM_003664.5(AP3B1):c.3131+5G>T

gnomAD frequency: 0.00053  dbSNP: rs191616060

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000553042	SCV000458276	uncertain significance	Hermansky-Pudlak syndrome 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553042	SCV000639577	uncertain significance	Hermansky-Pudlak syndrome 2	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change falls in intron 26 of the AP3B1 gene. It does not directly change the encoded amino acid sequence of the AP3B1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs191616060, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. 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: 354221). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155172	SCV003844554	uncertain significance	not specified	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: AP3B1 c.3131+5G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00038 in 251406 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome (0.00038 vs 0.0005), allowing no conclusion about variant significance. c.3131+5G>T has been reported in the literature in at least one individual affected with macrothrombocytopenia, however no second AP3B1 variant was identified (e.g., Montcrieff_2023). 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 was ascertained in the context of this evaluation (PMID: 36941763).ClinVar contains an entry for this variant (Variation ID: 354221). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV001699385	SCV004227087	uncertain significance	not provided	2022-06-21	criteria provided, single submitter	clinical testing	BS1
GenomeConnect - Invitae Patient Insights Network	RCV000553042	SCV001749906	not provided	Hermansky-Pudlak syndrome 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-07-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics, Academic Medical Center	RCV001699385	SCV001920699	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001699385	SCV001967335	uncertain significance	not provided		no assertion criteria provided	clinical testing