Submissions for variant NM_032383.5(HPS3):c.1870G>T (p.Glu624Ter)

gnomAD frequency: 0.00003  dbSNP: rs200079039

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001225137	SCV001397376	pathogenic	not provided	2024-10-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu624*) in the HPS3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS3 are known to be pathogenic (PMID: 11590544). This variant is present in population databases (rs200079039, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 812964). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001225137	SCV002513698	likely pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31898847, 32581362)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001827166	SCV003923225	pathogenic	Hermansky-Pudlak syndrome	2023-03-02	criteria provided, single submitter	clinical testing	Variant summary: HPS3 c.1870G>T (p.Glu624X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 5.2e-05 in 249792 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HPS3 causing Hermansky-Pudlak Syndrome (5.2e-05 vs 0.00055), allowing no conclusion about variant significance. c.1870G>T has been reported in the literature in individuals affected with Hermansky-Pudlak Syndrome (Huizing_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003467565	SCV004199992	pathogenic	Hermansky-Pudlak syndrome 3	2024-01-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003467565	SCV004236200	pathogenic	Hermansky-Pudlak syndrome 3	2023-06-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV003467565	SCV005662872	pathogenic	Hermansky-Pudlak syndrome 3	2024-03-25	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003902	SCV001161816	likely pathogenic	Hermansky-Pudlak syndrome 2		no assertion criteria provided	research
Natera, Inc.	RCV001827166	SCV002081513	pathogenic	Hermansky-Pudlak syndrome	2021-08-30	no assertion criteria provided	clinical testing