rs201227603 — HPS3 HPS3 Splice Donor Variant

Splice donor variant in HPS3 that disrupts exon 5 inclusion, causing Hermansky-Pudlak syndrome type 3 in homozygotes and conferring carrier status in heterozygotes; enriched in the Ashkenazi Jewish population.

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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.

Genotype Interpretations

What each possible genotype means for this variant.

GG Non-carrier Normal

No HPS3 disease allele detected

You carry two copies of the reference allele at rs201227603 in the HPS3 gene. This is the most common genotype globally, found in more than 99.99% of the general population. You have not inherited the founder splice donor variant associated with Hermansky-Pudlak syndrome type 3, and are not a carrier for this condition at this locus.

AG Carrier Carrier

One copy of the HPS3 splice donor variant detected — carrier status

Hermansky-Pudlak syndrome type 3 (HPS3) is caused by biallelic loss-of-function variants in the HPS3 gene, which encodes a subunit of the BLOC-2 intracellular trafficking complex. BLOC-2 is required for normal biogenesis of lysosome-related organelles, including platelet dense granules and melanosomes. In carriers with one functional copy, these organelles develop normally and no symptoms occur.

The rs201227603 variant destroys the splice donor site at intron 5, causing exon 5 skipping and non-functional protein from that allele. Because HPS3 follows strict autosomal recessive inheritance, a single carrier copy confers no detectable phenotype.

If you are of Ashkenazi Jewish ancestry, partner carrier screening is especially informative, since the estimated carrier frequency in that community is approximately 1 in 290 (based on a 0.172% allele frequency in gnomAD v4 Ashkenazi Jewish exomes). Standard Ashkenazi Jewish carrier screening panels may or may not include this specific variant — confirm coverage with your genetic counselor.

AA Homozygous Homozygous

Two copies of the HPS3 splice donor variant — consistent with Hermansky-Pudlak syndrome type 3

Hermansky-Pudlak syndrome type 3 results from complete loss of the BLOC-2 complex due to biallelic HPS3 variants. Without BLOC-2, two organelle systems fail:

  1. Melanosomes — cannot mature normally, causing oculocutaneous albinism with variable hypopigmentation of skin, hair, and eyes, reduced visual acuity, nystagmus, and photosensitivity. HPS3 albinism can be subtle enough to be initially diagnosed as ocular (not oculocutaneous) albinism.

  2. Platelet dense granules — fail to form, causing a delta storage pool deficiency. Platelets cannot release ADP and serotonin to recruit additional platelets, prolonging bleeding time. This presents as easy bruising, prolonged bleeding after cuts or dental work, and surgical hemorrhage risk. Platelet counts and morphology are typically normal — only platelet function testing (e.g., bleeding time, platelet aggregation studies, or electron microscopy showing absent dense granules) reveals the defect.

HPS3 does NOT involve BLOC-3 or AP-3 deficiency and therefore does not cause pulmonary fibrosis, a distinction that substantially improves prognosis compared to HPS1 and HPS4.

Annual surveillance includes ophthalmologic evaluation, skin examination for UV damage, and pulmonary function testing from age 20 onward (though pulmonary fibrosis is not expected, monitoring is standard of care across all HPS subtypes). Some HPS3 patients develop inflammatory bowel disease; colonoscopy is recommended for symptomatic individuals.