rs201227603 — HPS3 HPS3 Splice Donor Variant

HPS3: A Hidden Carrier Variant More Common in Ashkenazi Jews

The HPS3 gene encodes a subunit of the BLOC-2 complex¹¹ BLOC-2 complex
Biogenesis of Lysosome-related Organelles Complex 2, a multi-protein machine that organizes the intracellular trafficking of cargo into specialized organelles — including platelet dense granules (which store ADP and serotonin needed for blood clotting) and melanosomes (which produce and distribute skin and eye pigment). The rs201227603 variant disrupts a splice donor site at the start of intron 5, causing the cell's RNA-splicing machinery to skip exon 5 entirely and produce a non-functional protein. In people who inherit two copies, this causes Hermansky-Pudlak syndrome type 3 (HPS3)²² Hermansky-Pudlak syndrome type 3 (HPS3), a rare autosomal recessive disorder. In people who carry one copy, there are no symptoms — but the variant can be passed to children.

The Mechanism

rs201227603 lies at position chr3:149,145,547 (GRCh38) within the HPS3 gene on the plus strand. The G→A change at the +1 position of intron 5 destroys the canonical GT splice donor sequence³³ GT splice donor sequence
The GT dinucleotide at the start of almost every intron is essential for the spliceosome to recognize and excise the intron, causing exon 5 skipping and a frameshift that eliminates BLOC-2 function. Without functional BLOC-2, melanosomes fail to mature properly (causing oculocutaneous albinism) and platelet dense granules fail to form (causing a delta storage pool deficiency⁴⁴ delta storage pool deficiency
Platelets normally store ADP, ATP, and serotonin in dense granules; without them, the secondary wave of platelet aggregation fails, prolonging bleeding time). Critically, HPS3 does not affect the BLOC-3 or AP-3 complexes that are responsible for pulmonary fibrosis in HPS types 1, 2, and 4. HPS3 is among the milder HPS subtypes: hypopigmentation can be subtle enough to be missed, and pulmonary fibrosis is not a feature.

The Evidence

Huizing et al. (2001)⁵⁵ Huizing et al. (2001) first characterized the 1303+1G→A mutation (now rs201227603 in dbSNP) as a founder variant in Ashkenazi Jews, identifying five of eight non-Puerto Rican HPS3 patients as being of Ashkenazi descent and finding a carrier frequency of approximately 1 in 235 (0.43%) in anonymous Ashkenazi Jewish samples. Current gnomAD v4 exome data confirms the striking population stratification: the variant reaches an allele frequency of ~0.172% in Ashkenazi Jews, versus <0.001% in all other populations. Two copies would cause full HPS3 disease; in the Ashkenazi Jewish community, the expected disease frequency is approximately 1 in 33,000 births.

Huizing et al. (2020)⁶⁶ Huizing et al. (2020) comprehensively reviewed all 264 variants across 10 HPS genes and confirmed that pulmonary fibrosis is restricted to BLOC-3 (HPS1, HPS4) and AP-3 (HPS2) deficiencies — not to HPS3 (BLOC-2 deficiency) — making prognosis for HPS3 significantly better than for the most severe subtypes.

Marek-Yagel et al. (2022)⁷⁷ Marek-Yagel et al. (2022) described six compound heterozygous HPS3 patients carrying a splice site variant (c.1163+1G>A) and a large deletion; all presented with variable oculocutaneous albinism and ecchymoses, but none had pulmonary involvement, consistent with the mild BLOC-2 phenotype.

Practical Actions

For carriers (one copy): no health effects expected, but genetic counseling is valuable, particularly for Ashkenazi Jewish individuals planning families. If both partners carry the variant, each pregnancy has a 25% chance of producing an affected child.

For homozygous individuals (two copies, causing HPS3 disease): management centers on eye protection (albinism increases UV sensitivity and reduces visual acuity), bleeding precautions (dense granule deficiency prolongs bleeding time), and monitoring skin for UV-induced damage. Desmopressin (DDAVP) can correct the prolonged bleeding time prior to procedures. NSAIDs and aspirin must be strictly avoided, as they further impair platelet function.

Interactions

HPS3 disease requires biallelic loss-of-function in the HPS3 gene. Compound heterozygosity (one splice donor variant + one deletion or other loss-of-function allele) produces the same clinical picture as homozygosity. No published compound action is documented between rs201227603 and variants in other HPS genes, though digenic combinations are theoretically possible in pathway biology.