ClinVar Miner

Submissions for variant NM_000195.5(HPS1):c.988-1G>T

gnomAD frequency: 0.00001  dbSNP: rs764927038
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001387339 SCV001587943 pathogenic not provided 2023-07-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change affects an acceptor splice site in intron 11 of the HPS1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs764927038, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with Hermansky-Pudlak syndrome (PMID: 19398212). ClinVar contains an entry for this variant (Variation ID: 1074133). Studies have shown that disruption of this splice site results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 19398212).
GeneDx RCV001387339 SCV001822224 likely pathogenic not provided 2023-04-03 criteria provided, single submitter clinical testing Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 31898847, 19398212)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001826175 SCV002097059 likely pathogenic Hermansky-Pudlak syndrome 2021-11-29 criteria provided, single submitter curation The c.988-1G>T variant in HPS1 has been reported in 1 individual, in the homozygous state, with Hermansky-Pudlak syndrome (PMID: 19398212), and has been identified in 0.0098% (3/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs764927038). 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#: 1074133) and has been interpreted as pathogenic by Invitae. In vitro functional studies provide some evidence that the c.988-1G>T variant may slightly impact protein function (PMID: 19398212). However, these types of assays may not accurately represent biological function. This variant is located in the 5' 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_moderate, PM2_supporting, PM3_supporting, PS3_moderate (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001826175 SCV003928842 pathogenic Hermansky-Pudlak syndrome 2023-04-04 criteria provided, single submitter clinical testing Variant summary: HPS1 c.988-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' acceptor site. Experimental evidence have shown disruption of this splice site results in exon 12 skipping, leading to an inframe deletion of 56 amino acids from the encoded HPS1 protein (example: Vincent_2009). The variant allele was found at a frequency of 1.2e-05 in 251112 control chromosomes (gnomAD). c.988-1G>T has been reported in the literature in an individual affected with Hermansky-Pudlak Syndrome (example: Vincent_2009). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and allclassified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003469730 SCV004199937 pathogenic Hermansky-Pudlak syndrome 1 2023-08-04 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003469730 SCV004236190 pathogenic Hermansky-Pudlak syndrome 1 2023-05-03 criteria provided, single submitter clinical testing

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