Submissions for variant NM_032122.5(DTNBP1):c.162G>A (p.Arg54=)

gnomAD frequency: 0.00077  dbSNP: rs77460377

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000195186	SCV000247197	uncertain significance	not specified	2015-06-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000195186	SCV002104021	likely benign	not specified	2022-02-15	criteria provided, single submitter	clinical testing	Variant summary: DTNBP1 c.162G>A (p.Arg54Arg) alters a 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 abolishes a 5' splicing donor site. Three predict the variant weakens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00066 in 250182 control chromosomes. The observed variant frequency is approximately 4.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in DTNBP1 causing Hermansky-Pudlak Syndrome phenotype (0.00016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.162G>A in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae	RCV001852553	SCV002278108	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change affects codon 54 of the DTNBP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DTNBP1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs77460377, gnomAD 0.1%), 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 DTNBP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 210857). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.