Table 5:

HPS3 Gene Variants Associated with Hermansky-Pudlak Syndrome Type 3 (HPS-3)

No	mRNA NM_032383.5	Amino Acid NP_115759.2	Exon/Intron	Variant Type 1	Ethnic Background 2	References and Footnotes
1	c.-2993_217+692del 3	-	5’UTR Intron 1	Indel	Central Puerto Rican	(Anikster et al., 2001; Torres-Serrant et al., 2010) 3,4
2	c.15C>G	p.Tyr5*	Exon 1	Nonsense	Dutch, German	novel 5,6
3	c.87dupG	p.Arg30Alafs*2	Exon 1	Frameshift	Japanese	(Saito et al., 2019)
4	c.319C>T	p.Arg107*	Exon 1	Nonsense	Japanese	(Okamura et al., 2019) 7
5	c.437_439delGAG	p.Gly146del	Exon 1	Indel	Japanese	(Okamura et al., 2019) 7,8
6	c.712+2T>C	IVS2+2	Intron 2	Splice site	Chinese	(A. Wei et al., 2016) 7
7	c.726_727insTGCCTTACATC	p.Ile243Cysfs*41	Exon 3	Indel	Puerto Rican	novel 4,5
8	c.728_729insA	p.Ser244Phefs*4	Exon 3	Frameshift	Italian, Sicilian	(Boissy et al., 2005) 9
9	c.851_852delGA	p.Arg284Lysfs*11	Exon 3	Indel	Portuguese	novel 5,11
10	c.868C>T	p.Gln290*	Exon 3	Nonsense	Arabic	(Khan et al., 2016) 7
11	c.885–1G>A	IVS3–1G>A	Intron 3	Splice site	Libyan	(Thielen et al., 2010)
12	c.1012G>T	p.Glu338*	Exon 5	Nonsense	Caucasian	novel 5,12
13	c.1107_1119del13insC	p.Pro370_Ser373del	Exon 5	Indel	French-Canadian	novel 5,13,14
14	c.1153_1160del8	p.Val385Lysfs*2	Exon 5	Indel	Middle-Eastern	(Trujillano et al., 2017) 7
15	c.1163+1G>A	IVS5+1G>A	Intron 5	Splice site	Ashkenazi Jewish	(Huizing et al., 2001)
16	c.1189C>T	p.Arg397Trp	Exon 6	Missense	Canadian, Caucasian, Chinese, German, Japanese, Polish, Russian, Swiss	(Huizing et al., 2001; Nazarian et al., 2008; Okamura et al., 2019; Wei et al., 2016) 7,12,15
17	c.1195A>G/ c.1199_1200insATTGC	p.Ser399Gly/ p.Ala401Leufs*16	Exon 6	Indel	English, German, Irish, Scottish, Cherokee	novel 5,16
18	c.1291delC	p.Leu431Phefs*3	Exon 7	Frameshift	Japanese	(Okamura et al., 2019) 7,8
19	c.1426dupA	p.Ile476Asnfs*8	Exon 8	Frameshift	Japanese	(Saito et al., 2019)
20	c.1509G>A	p.Met503Ile	Exon 8	Missense-Splice site	Pakistani	(Yousaf et al., 2016) 7,17
21	c.1555_1595dup41	p.Leu533Phefs*10	Exon 8	Indel	Chinese	(Power et al., 2019)
22	c.1673T>C	p.Leu558Pro	Exon 8	Missense	-	(Lasseaux et al., 2018) 7
23	c.1691+1G>A	IVS9+1G>A	Intron 9	Splice site	French-Canadian	novel 5,13
24	c.1691+2T>G	IVS9+2T>G	Intron 9	Splice site	Ashkenazi Jewish	(Huizing et al., 2001)
25	c.1838C>G	p.Ser613*	Exon 10	Nonsense	Chinese	(Wei et al., 2019) 7
26	c.1870G>T	p.Glu624*	Exon 10	Nonsense	German, Irish	novel 5,18
27	c.2208_2209delTC	p.Gln737Alafs*20	Exon 12	Indel	Chinese	(Wei et al., 2016) 7
28	c.2464C>T	p.Arg822*	Exon 13	Nonsense	Dutch, German, Portuguese, Spanish	(Bastida et al., 2019) 6,7,11
29	c.2482–2A>G	IVS13–2A>G	Intron 13	Splice site	Irish/German	(Huizing et al., 2001)
30	c.2589+1G>C	IVS14+1G>C	Intron14	Splice site	German/Swiss	(Huizing et al., 2001)
31	c.2589+1G>T	IVS14+1G>T	Intron14	Splice site	German, Irish	novel 5,18
32	c.2628delT	p.Ile877Phefs*25	Exon 15	Frameshift	-	(Lasseaux et al., 2018) 7
33	c.2733delG	p.Leu912*	Exon 15	Frameshift	English, German, Irish, Scottish, Cherokee	novel 5,16,19
34	c.2739_2742delGAGA	p.Glu913Aspfs*14	Exon 15	Indel	-	novel 5,14
35	c.2771delA	p.Asn924Ilefs*4	Exon 15	Frameshift	Turkish	(Sandrock-Lang et al., 2017)
36	c.2805G>A	p.Trp935*	Exon 16	Nonsense	Chinese	(Wei et al., 2016) 7
37	c.2888–1612G>A21	IVS16–1612G>A p.Glu963Alafs*24	Intron16	Splice site	English, Irish	(Huizing et al., 2001) 20

¹When deletion/insertion is 1 nucleotide it is named Frame shift, when larger it is named Indel.

²Extracted from literature reference. ‘-‘ = unreported.

³This HPS3 3.9-kb deletion occurs within two Alu repeats, encompassing exon 1 and originates from a genetic isolate of central Puerto Rico (Anikster et al., 2001). Current nomenclature (as annotated in ClinVar) for this deletion is NM_032383.5(HPS3):c.-2993_217+692del or NC_000003.12:g.149126714_149130632del (GRCh38) or NG_009847.1:g.2131_6049del.

⁴This HPS3 variant was identified in one unreported female subject of Puerto Rican descent in the NIH cohort. This subject was compound heterozygous for c.726delinsTGCCTTACATC and the Central Puerto Rican founder variant g.del3.9-kb.

⁵novel = previously unreported variant detected in the NIH HPS cohort.

⁶This HPS3 variant was identified in one unreported male subject of Dutch-German descent in the NIH HPS cohort. This subject was compound heterozygous for c.15C>G and c.2464C>T.

⁷At least one of the reported cases with this variant was identified by next generation sequencing.

⁸The HPS3 variant c.437_439delGAG occurred compound heterozygous with c.1291delC in a subject of Japanese descent who also had non-segmental vitiligo (Okamura et al., 2019).

⁹This HPS3 variant c.728insA was identified homozygous in one unreported female subject of Sicilian decent in the NIH HPS cohort.

¹⁰Gray highlight: missense variant. See Supplemental Table S1 for pathogenicity description.

¹¹This HPS3 variant was identified in one unreported male subject of Portuguese decent in the NIH HPS cohort. This subject was compound heterozygous for c.851_852delGA and c.2464C>T.

¹²This HPS3 variant was identified in one unreported female subject of Caucasian descent in the NIH HPS cohort. This subject was compound heterozygous for c.1012G>T and c.1189C>T.

¹³This HPS3 variant was identified in one unreported female subject of French-Canadian descent in the NIH HPS cohort. This subject was compound heterozygous for c.1107_1119del13insC and c.1691+1G>A.

¹⁴This HPS3 variant was identified in one unreported female subject of in the NIH cohort (referred by Dr. Doherty, Carilion Clinic, Roanoke, VA). This subject was compound heterozygous for c.1107_1119del13insC and c.2739_2742delGAGA.

¹⁵This HPS3 variant c.1189C>T was identified homozygous in one unreported female subject of Canadian-Polish-Russian decent in the NIH cohort. Cells of this patient showed destabilized BLOC-2 assembly, likely due to pathogenicity of this variant (Nazarian et al., 2008).

¹⁶This HPS3 variant was identified in one unreported female subject of English-German-Irish-Scottish-Cherokee descent in the NIH HPS cohort. This subject was compound heterozygous for c.1195A>G/1199insATTGC and c.2733delG.

¹⁷This (missense) HPS3 variant c.1509G>A; p.Met503Ile occurs at the exon8/intron 8 splice site junction and may affect splicing. This variant occurs homozygous in 4 subjects of a consanguineous Pakistani family (Yousaf et al., 2016).

¹⁸This HPS3 variant was identified in one unreported male subject of German-Irish descent. This subject was compound heterozygous for c.1870G>T and c.2589+1G>T.

¹⁹Subject HPS34 of English-Irish descent in (Huizing et al., 2001) was reported heterozygous for c.2887+2500G>A. We found c.2733delG to be the second HPS3 variant in this subject.

²⁰This HPS3 variant was reported in an alternative nomenclature as c.2887+2500G>A. This intronic variant introduces a new consensus splice site that results in insertion of 89-bp (a ‘pseudoexon’) in the patient’s cDNA (Huizing et al., 2001; Vorechovsky, 2010).