Submissions for variant NM_003664.5(AP3B1):c.2188C>T (p.Arg730Trp)

gnomAD frequency: 0.00032  dbSNP: rs141102178

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000640579	SCV000458291	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	RCV000640579	SCV000762173	uncertain significance	Hermansky-Pudlak syndrome 2	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 730 of the AP3B1 protein (p.Arg730Trp). This variant is present in population databases (rs141102178, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with a mild platelet defect (PMID: 32935436). ClinVar contains an entry for this variant (Variation ID: 354231). 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 tolerated. 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, Fulgent Genetics	RCV000640579	SCV000895717	uncertain significance	Hermansky-Pudlak syndrome 2	2022-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001591018	SCV001823250	uncertain significance	not provided	2020-12-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with an inherited bleeding disorder, but additional clinical information, familial segregation, and functional studies were not available (Almazani et al., 2020); This variant is associated with the following publications: (PMID: 32935436)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238939	SCV005887263	uncertain significance	not specified	2025-01-14	criteria provided, single submitter	clinical testing	Variant summary: AP3B1 c.2188C>T (p.Arg730Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 251442 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome (0.00047 vs 0.0005), allowing no conclusion about variant significance. c.2188C>T has been reported in the literature in individuals affected with mild platelet disorder (Almazni_2020). 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 have been ascertained in the context of this evaluation (PMID: 32935436). ClinVar contains an entry for this variant (Variation ID: 354231). Based on the evidence outlined above, the variant was classified as uncertain significance.
Birmingham Platelet Group; University of Birmingham	RCV001270588	SCV001450887	uncertain significance	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003950256	SCV004758457	likely benign	AP3B1-related disorder	2023-06-02	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).