ClinVar Genomic variation as it relates to human health

The c.1163+1G>A variant, also known as c.1303+1G>A, in HPS3 has been reported in the homozygous state in 3 individuals with Hermansky Pudlak syndrome type 3 and in the compound heterozygous state with other splice site variants in 2 individ uals with Hermansky Pudlak syndrome type 3, all of whom had Ashkenazi Jewish anc estry (Huizing 2001). It has also been identified in 0.17% (17/10150) of Ashkena zi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence. Stud ies have demonstrated that this variant cases skipping of exon 5, resulting in a premature translational stop at codon 350, which is predicted to produce a trun cated or absent protein (Huizing 2001). Loss of function of the HPS3 gene is an established disease mechanism in Hermansky Pudlak syndrome type 3, which is a mi lder form of Hermansky Pudlak syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Hermansky Pudlak syndrome . ACMG/AMP Criteria applied: PVS1, PM3_Strong, PS3_Supporting.

NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant classified as pathogenic in the context of Hermansky-Pudlak syndrome type 3. Please note that c.1163+1G>A may be associated with a mild form of the disease. c.1163+1G>A has been observed in cases with relevant disease (PMID: 11590544). Functional assessments of this variant are available in the literature (PMID: 11590544). c.1163+1G>A has been observed in population frequency databases (gnomAD: ASJ 0.16%). In summary, NM_032383.3(HPS3):c.1163+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, has functional support for pathogenicity, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

This sequence change affects a donor splice site in intron 5 of the HPS3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs201227603, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individuals with Hermansky-Pudlak syndrome (HPS) (PMID: 11590544). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 11590544). This variant is also known as 1303+1G>A. ClinVar contains an entry for this variant (Variation ID: 4609). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (PMID: 11590544). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The HPS3 c.1163+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also referred to as c.1303+1G>A in the literature, results in skipping of exon 5 during mRNA splicing (Huizing et al. 2001. PubMed ID: 11590544) and has been reported in the homozygous or compound heterozygous state in individuals of Ashkenazi Jewish ancestry with Hermansky-Pudlak syndrome (Huizing et al. 2001. PubMed ID: 11590544; Marek-Yagel et al. 2022. PubMed ID: 36046236). This variant is reported in 0.15% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Variants that disrupt the consensus splice donor site in HPS3 are expected to be pathogenic. This variant is interpreted as pathogenic.