Submissions for variant NM_000195.5(HPS1):c.391C>T (p.Arg131Ter)

gnomAD frequency: 0.00001  dbSNP: rs281865076

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206990	SCV001378325	pathogenic	not provided	2024-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg131*) 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). This variant is present in population databases (rs281865076, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with HPS1-related conditions (PMID: 14510955, 21458243). ClinVar contains an entry for this variant (Variation ID: 21104). For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001804742	SCV002051799	pathogenic	Hermansky-Pudlak syndrome 1	2021-10-20	criteria provided, single submitter	clinical testing	HPS1 c.391C>T has been reported in multiple individuals with Hermansky-Pudlak syndrome 1. This variant (rs281865076) is rare (<0.1%) in a large population dataset (gnomAD: 1/251160 total alleles; 0.0004%; no homozygotes) and has been reported in ClinVar. This nonsense variant results in a premature stop codon in exon 5 likely leading to nonsense-mediated decay and lack of protein production. We consider HPS1 c.391C>T to be pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001826482	SCV002097065	pathogenic	Hermansky-Pudlak syndrome	2021-11-29	criteria provided, single submitter	curation	The p.Arg131Ter variant in HPS1 has been reported in 2 individuals with Hermansky-Pudlak syndrome (PMID: 14510955, 21458243), and has been identified in 0.003% (1/34584) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs281865076). 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 was found to be de novo in 1 individual with confirmed paternity and maternity (PMID: 14510955). Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg131Ter variant is pathogenic (VariationID: 5278; PMID: 14510955). This variant has also been reported in ClinVar (Variation ID#: 21104) and has been interpreted as pathogenic by GeneReviews and Invitae. In vitro functional studies provide some evidence that the p.Arg131Ter variant may impact protein function (PMID: 14510955). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 131, which is 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, PM2_supporting, PVS1, PS3_moderate, PS2 (Richards 2015).
Fulgent Genetics, Fulgent Genetics	RCV001804742	SCV002804645	pathogenic	Hermansky-Pudlak syndrome 1	2021-08-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001804742	SCV004199932	pathogenic	Hermansky-Pudlak syndrome 1	2023-11-18	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001826482	SCV002091683	pathogenic	Hermansky-Pudlak syndrome	2021-10-11	no assertion criteria provided	clinical testing