Submissions for variant NM_000195.5(HPS1):c.1406A>G (p.Gln469Arg)

gnomAD frequency: 0.00133  dbSNP: rs148978269

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000888751	SCV001032404	likely benign	not provided	2024-01-24	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818649	SCV002067228	likely benign	not specified	2019-12-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002495377	SCV002808044	likely benign	Hermansky-Pudlak syndrome 1	2021-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000888751	SCV003803585	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published in association with HPS1-related Hermansky-Pudlak syndrome to our knowledge; This variant is associated with the following publications: (PMID: 28719003)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818649	SCV003845136	likely benign	not specified	2023-02-23	criteria provided, single submitter	clinical testing	Variant summary: HPS1 c.1406A>G (p.Gln469Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 250958 control chromosomes, predominantly at a frequency of 0.0048 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in HPS1 causing Hermansky-Pudlak Syndrome phenotype (0.00096), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1406A>G in individuals affected with Hermansky-Pudlak Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) have cited the variant, with four submitters classifying the variant as likely benign and one submitter classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003910533	SCV004726262	likely benign	HPS1-related disorder	2021-04-26	criteria provided, single submitter	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).
Ambry Genetics	RCV004028378	SCV004882584	uncertain significance	Inborn genetic diseases	2021-10-27	criteria provided, single submitter	clinical testing	The c.1406A>G (p.Q469R) alteration is located in exon 15 (coding exon 13) of the HPS1 gene. This alteration results from a A to G substitution at nucleotide position 1406, causing the glutamine (Q) at amino acid position 469 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001273028	SCV001455563	likely benign	Hermansky-Pudlak syndrome	2020-09-16	no assertion criteria provided	clinical testing