Submissions for variant NM_000195.5(HPS1):c.1189del (p.Gln397fs) (rs281865084)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Clinical Services Laboratory,Illumina	RCV000020181	SCV000359659	likely pathogenic	Hermansky-Pudlak syndrome 1	2017-04-27	criteria provided, single submitter	clinical testing	The HPS1 c.1189delC (p.Gln397SerfsTer2) variant results in a frameshift and is predicted to cause a premature termination of the protein. The variant is reported in six studies in which it is found in a total of nine out of 43 individuals with Hermansky-Pudlak syndrome (HPS), including two homozygotes, one hemizygote, and six compound heterozygotes, and in four unaffected heterozygous family members (Oh et al. 1998; Shotelersuk et al. 1998; Griffin et al. 2005; Huizing et al. 2007; Sandrock et al. 2010; Westmoreland et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Northern blot analysis of fibroblasts from the hemizygous individual showed significantly reduced HPS RNA (Shotelersuk et al. 1998). Based on the collective evidence, the p.Gln397SerfsTer2 variant is classified as pathogenic for Hermansky-Pudlak syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000851664	SCV000899448	pathogenic	Hermansky-Pudlak syndrome	2019-02-01	criteria provided, single submitter	research
Invitae	RCV000796076	SCV000935571	pathogenic	not provided	2018-08-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln397Serfs*2) in the HPS1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs281865084, ExAC 0.01%). This variant has been observed in several individuals affected with HPS1-related conditions (PMID: 9497254, 20514622, 28081892). This variant is also known as E397delC in the literature. ClinVar contains an entry for this variant (Variation ID: 21091). Loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000020181	SCV000040514	pathologic	Hermansky-Pudlak syndrome 1	2012-10-11	no assertion criteria provided	curation	Converted during submission to Pathogenic.