ClinVar Miner

Submissions for variant NM_003664.5(AP3B1):c.1069A>G (p.Ile357Val)

gnomAD frequency: 0.00274  dbSNP: rs142025324
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services,Illumina RCV001081024 SCV000458308 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.
Invitae RCV001081024 SCV000639565 likely benign Hermansky-Pudlak syndrome 2 2021-12-08 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000545916 SCV001154429 likely benign not provided 2019-02-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV001821080 SCV002069766 uncertain significance not specified 2017-10-25 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001821080 SCV002103709 likely benign not specified 2022-02-17 criteria provided, single submitter clinical testing Variant summary: AP3B1 c.1069A>G (p.Ile357Val) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0017 in 251064 control chromosomes, predominantly at a frequency of 0.0024 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in AP3B1 causing Hermansky-Pudlak Syndrome phenotype (0.0005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1069A>G in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign, n=2; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory,The Hospital for Sick Children RCV002261077 SCV002542655 likely benign Autoinflammatory syndrome 2020-01-01 criteria provided, single submitter clinical testing
Clinical Genetics, Academic Medical Center RCV000545916 SCV001923360 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000545916 SCV001926786 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000545916 SCV001971351 likely benign not provided no assertion criteria provided clinical testing

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