Submissions for variant NM_000195.5(HPS1):c.1375del (p.Ser459fs)

Minimum review status:		Collection method:
Minimum conflict level: Report conflict between different conditions
		ClinVar version:

Total submissions: 4

Download table as spreadsheet

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001829292	SCV002097055	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.Ser459fs variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 15952982), segregated with disease in 1 affected relative from 1 family (PMID: 15952982) and has been identified in 0.0009% (1/112934) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1278076617). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 21093) and has been interpreted as Pathogenic by GeneReviews. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 459 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PM3_supporting, PM2_supporting, PVS1 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002542778	SCV002936022	pathogenic	not provided	2022-10-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1341378). This premature translational stop signal has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 15952982). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ser459Valfs*16) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271).
Baylor Genetics	RCV003475104	SCV004199979	pathogenic	Hermansky-Pudlak syndrome 1	2022-02-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV003475104	SCV005664340	pathogenic	Hermansky-Pudlak syndrome 1	2024-05-21	criteria provided, single submitter	clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.