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

gnomAD frequency: 0.00001  dbSNP: rs764927038

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	2024-01-16	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
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003469730	SCV005086550	pathogenic	Hermansky-Pudlak syndrome 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Hermansky-Pudlak syndrome 1 (MIM#203300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR on patient melanocytes has confirmed the inframe skipping of exon 12 (PMID: 19398212). (SP) 0252 - This variant is homozygous. However, there appears to be an overlapping deletion. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0600 - Variant affects part of the Fuz_longin_2 domain (DECIPHER). (I) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic (ClinVar), and observed in a homozygous individual with Hermansky-Pudlak syndrome (PMID: 19398212). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign