Submissions for variant NM_000195.5(HPS1):c.398+2T>C

gnomAD frequency: 0.00002  dbSNP: rs1486224265

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519155	SCV000616744	pathogenic	not provided	2017-03-10	criteria provided, single submitter	clinical testing	The c.398+2T>C variant in the HPS1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.398+2T>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.398+2T>C as a pathogenic variant.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001829480	SCV002097072	likely pathogenic	Hermansky-Pudlak syndrome	2021-12-10	criteria provided, single submitter	curation	The c.398+2T>C variant in HPS1 has been reported in 1 individual, in the compound heterozygous state, with Hermansky-Pudlak syndrome (PMID: 31898847), segregated with disease in 1 affected relative from 1 family (PMID: 31898847), and has been identified in 0.01% (4/34584) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1486224265). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 6449037) and has been interpreted as pathogenic by GeneDx. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the HPS1 gene is an established disease mechanism in autosomal recessive Hermansky-Pudlak syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive Hermansky-Pudlak syndrome. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Invitae	RCV000519155	SCV002261046	likely pathogenic	not provided	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the HPS1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HPS1 are known to be pathogenic (PMID: 12442288, 16185271). This variant is present in population databases (no rsID available, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 31898847). ClinVar contains an entry for this variant (Variation ID: 449037). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003470646	SCV004199966	pathogenic	Hermansky-Pudlak syndrome 1	2023-12-27	criteria provided, single submitter	clinical testing