Table 3:

HPS1 Pathogenic Gene Variants Associated with Hermansky-Pudlak Syndrome Type 1 (HPS-1)

#	mRNA NM_000195.5	Amino Acid NP_000186.2	Exon/Intron	Variant Type 1	Ethnic Background 2	References and Footnotes
1	del exon 2 3	-	Exon 2	Indel	-	(Lasseaux et al., 2018) 4
2	c.2T>A	p.Met1Lys 5	Exon 3	Start-loss	-	(Lasseaux et al., 2018) 4,5
3	c.9delC	p.Cys3Trpfs*26	Exon 3	Frameshift	Chinese	(Power et al., 2019)
4	c.34dupG	p.Glu12Glyfs*12	Exon 3	Frameshift	-	(Lasseaux et al., 2018) 4
5	c.81delG	p.Leu28*	Exon 3	Nonsense	Korean	(Sim et al., 2019)
6	del 121-bp 3,6	p.Pro41Aspfs*12	Intron 3/Exon 4	Indel	Pakistani	(Yousaf et al., 2016) 4,6
7	c.97_100delTCAG	p.Ser33Argfs*18	Exon 3	Indel	English, Irish, German, Scottish	(Sandrock et al., 2010) 7
8	c.166_168delATC	p.Ile56del	Exon 4	Indel	Afghan	(Oh et al., 1998)
9	c.212_215delGCTT	p.Cys71Serfs*52	Exon 4	Indel	-	(Lasseaux et al., 2018) 4
10	c.217delT	p.Ser73Profs*51	Exon 4	Frameshift	-	(Lasseaux et al., 2018) 4
11	c.255+5G>A	IVS4+5G>A (p.Tyr81Leufs*38)	Intron4	Splice site	Iranian	(Ghafouri-Fard et al., 2016)
12	c.288delT	p.Asp97Thrfs*27	Exon 5	Frameshift	Japanese	(Ito et al., 2005; Spritz & Oh, 1999)
13	c.316C>G	p.Arg106Gly 8	Exon 5	Missense	Chinese	(Wei et al., 2016) 4
14	c.344T>C	p.Leu115Pro	Exon 5	Missense	Arabic	(Khan et al., 2016) 4
15	c.355delC	p.His119Thr*5	Exon 5	Frameshift	German, Polish, Russian	(Hermos et al., 2002; Sandrock et al., 2010)
16	c.391C>T	p.Arg131*	Exon 5	Nonsense	Caucasian, Chinese, Spanish	(Arcot Sadagopan et al., 2017; Gonzalez-Conejero et al., 2003; Hermos et al., 2002; Wei et al., 2011)
17	c.397G>T	p.Glu133*	Exon 5	Nonsense	German, Italian, Ukrainian	(Hermos et al., 2002; Shotelersuk et al., 1998)
18	c.398+2T>C	IVS5+2T>C	Intron 5	Splice site	Mexican	novel 4,9,10
19	c.398+5G>A	IVS5+5G>A	Intron 5	Splice site	Chinese, Indian, Japanese	(Furuhashi et al., 2014; Horikawa et al., 2000; Ito et al., 2005; Li et al., 2016; Mai et al., 2019; Natsuga et al., 2005; Oh et al., 1998; Suzuki et al., 2004; Tanaka et al., 2015; Vincent et al., 2009; Wei et al., 2016) 4,11
20	c.418delG	p.Ala140Argfs*35	Exon 6	Frameshift	European	(Hermos et al., 2002)
21	c.461G>A	p.Trp154*	Exon 6	Nonsense	Dutch	(Thielen et al., 2010)
22	c.467_476del10	p.Tyr156Cysfs*16	Exon 6	Indel	Honduran, Salvadoran	(Carmona-Rivera, Golas, et al., 2011)
23	c.505G>A	p.Glu169Lys	Exon 6	Missense- Splice site	Arabic	(Khan et al., 2016) 4,12
24	c.507G>A	p.Glu169Glu 13	Exon 6	Splice site	African-American	(Merideth et al., 2009) 13
25	c.507+1G>A	IVS6+1G>A	Intron 6	Splice site	Japanese	(Lasseaux et al., 2018; Natsuga et al., 2005) 14
26	c.517C>T	p.Arg173*	Exon 7	Nonsense	Chinese	(Wei et al., 2016) 4
27	c.532dupC	p.Gln178Profs*4	Exon 7	Frameshift	Japanese	(Ito et al., 2005; Iwakawa et al., 2005)
28	c.610G>T	p.Glu204*	Exon 7	Nonsense	Spanish	(Sanchez-Guiu et al., 2014)
29	c.640delC	p.His214Thrfs*117	Exon 7	Frameshift	Chinese	(Wei et al., 2019) 4
30	c.695C>T	p.Ala232Val	Exon 8	Missense	Arabic	(Khan et al., 2016) 4
31	c.716T>C	p.Leu239Pro	Exon 8	Missense	Dutch, German, Irish	(Hermos et al., 2002; Lasseaux et al., 2018; Thielen et al., 2010) 4,15
32	c.868–2A>G	IVS9–2A>G	Intron 9	Splice site	Chinese	(Wei et al., 2019) 4
33	c.937G>A	p.Gly313Ser	Exon 10	Missense- Splice site	Puerto Rican	(Carmona-Rivera, Hess, et al., 2011; Lasseaux et al., 2018) 4,16
34	c.956delA	p.Glu319Glyfs*12	Exon 11	Frameshift	Chinese	(Wei et al., 2019) 4
35	c.962delG	p.Gly321Alafs*10	Exon 11	Frameshift	Ukrainian	(Oh et al., 1998)
36	c.962dupG	p.Thr322Hisfs*131	Exon 11	Frameshift	Japanese	(Horikawa et al., 2000)
37	c.972delC	p.Met325Trpfs*6	Exon 11	Frameshift	African-American, Chinese, Japanese, Mexican, Northern European, Puerto Rican	(Carmona-Rivera, Golas, et al., 2011; Carmona-Rivera, Hess, et al., 2011; Hermos et al., 2002; Lasseaux et al., 2018; Merideth et al., 2009; Oh et al., 1996; Oh et al., 1998; Shotelersuk et al., 1998; Wei et al., 2016) 4,17
38	c.972dupC	p.Met325Hisfs*128	Exon 11	Frameshift	Chinese, Japanese, Northern European, Swiss	(Hermos et al., 2002; Lasseaux et al., 2018; Oh et al., 1996; Oh et al., 1998; Okamura et al., 2019; Wei et al., 2010; Wei et al., 2011; Wei et al., 2019) 4,,17,18
39	c.988–1 G>T	IVS11–1G>T	Intron 11	Splice site	Indian	(Vincent et al., 2009) 19
40	del13,966-bp/ins49-bp 3	p.Gln329fs	Intron 11- Exon 20	Indel	Northern European	(Griffin et al., 2005)
41	c.1080C>G	p.Ser360Arg	Exon 12	Missense	Canadian, German, Irish, Scottish, Swedish, Ukrainian	novel 4,9,20
42	c.1132_1138delATCAACC	p.Ile378Trpfs*4	Exon 12	Indel	Chinese	(Wei et al., 2019) 4
43	c.1189delC	p.Gln397Serfs*2	Exon 13	Frameshift	American, Hispanic, Northern European, Russian, Ukrainian	(Doubkova et al., 2019; Griffin et al., 2005; Hermos et al., 2002; Lasseaux et al., 2018; Oh et al., 1998; Sandrock et al., 2010; Shotelersuk et al., 1998) 4,17,20–24
44	c.1228A>T	p.Lys410*	Exon 13	Nonsense	Ukrainian	novel 9,21
45	c.1276_1279dupGGAG	p.Asp427Glyfs*27	Exon 13	Indel	Chinese	(Wei et al., 2019) 4
46	c.1294_1298delATGGAinsT	p.Met432Serfs*42	Exon 13	Indel	Mexican	novel 4,9,10
47	c.1323dupA	p.Gln442Thrfs* 11	Exon 13	Frameshift	Japanese	(Oh et al., 1996)
48	c.1342T>C	p.Trp448Arg	Exon 14	Missense	Pakistani	(Yousaf et al., 2016) 4
49	c.[1375delA; c.1388C>A]	p.Ser459Valfs*16	Exon 14	Frameshift	Northern European	(Hermos et al., 2002)
50	c.1423_1428delAAGCGG	p.Lys475_Arg476del	Exon 15	Indel	-	(Lasseaux et al., 2018) 4
51	c.1457_1460dupTTCT	p.Thr488Serfs*95	Exon 15	Indel	Chinese	(Wei et al., 2016) 4
52	c.1472_1487dup16 24	p.His497Glnfs*90	Exon 15	Indel	NW-Puerto Rican	(Hermos et al., 2002; Oh et al., 1996; Santiago Borrero et al., 2006) 25
53	c.1477delA	p.Arg493Glyfs*22	Exon 15	Frameshift	Chinese	(Power et al., 2019)
54	c.1507C>T	p.Gln503*	Exon 15	Nonsense	Caucasian	(Doubkova et al., 2019) 4
55	del exon 15	deletion	Exon 15	Indel	Chinese	(Wei et al., 2019) 4
56	del exon 15–18 3	deletion	Ex15–18	Indel	Chinese	(Wei et al., 2016) 4
57	c.1639G>T/c.1645C>T	p.Val547Leu/ p.Arg549Cys	Exon 17	Missense	Assyrian, English, German, Irish	(Nazarian et al., 2008) 15,26
58	c.1691delA	p.Lys564Argfs*22	Exon 17	Frameshift	Japanese	(Ito et al., 2005)
59	c.1744–2A>C	IVS17–2A>C	Intron17	Splice site	Caucasian, English, German, Irish	(Hermos et al., 2002; Lasseaux et al., 2018; McElvaney et al., 2018; Oetting & King, 1999) 4,22,27
60	c.1749G>A	p.Trp583*	Exon 18	Nonsense	Japanese, Arabic	(Ito et al., 2005) 4,28
61	c.1763T>C	p.Leu588Pro	Exon 18	Missense	Japanese	(Okamura et al., 2019) 4
62	c.1787G>T	p.Gly596Val	Exon 18	Missense	Japanese	(Okamura et al., 2019; Takeuchi et al., 2014) 4
63	c.1857+2T>C	IVS18+2T>C	Intron 18	Splice site	Irish	(McElvaney et al., 2018) 27
64	c.1858–1G>A	IVS18–1G>A	Intron18	Splice site	Dutch, French, German, Irish, Native American	novel 9,29
65	c.1887delC	p.Val630Serfs*95	Exon 19	Frameshift	Chinese	(Wei et al., 2011)
66	c.1932delC	p.Tyr645Thrfs*80	Exon 19	Frameshift	Chinese	(Wei, Lian, Wang, & Li, 2009; Wei, Zang, Zhang, Yang, & Li, 2015; Wei et al., 2019) 4
67	c.1937A>G	p.Tyr646Cys	Exon 19	Missense	English, Irish, Scottish	novel 9,15,24
68	c.1941–2A>G	IVS19–2A>G	Intron 19	Splice site	Japanese	(Okamura et al., 2019) 4
69	c.1996G>A	p.Glu666Lys	Exon 20	Missense	Korean	(Sim et al., 2019)
70	c.1996G>C	p.Glu666Gln	Exon 20	Missense	-	(Lasseaux et al., 2018) 4
71	c.1996G>T	p.Glu666*	Exon 20	Nonsense	Scottish	(Oh et al., 1998)
72	c.2003T>C	p.Leu668Pro	Exon 20	Missense	Chinese, Japanese	(Ito et al., 2005; Iwata et al., 2017; Kanazu et al., 2014; Mai et al., 2019; Okamura et al., 2019; Wei et al., 2016) 4
73	c.2010_2037del28	p.His671Trpfs*45 29	Exon 20	Indel	-	(Lasseaux et al., 2018) 4,30
74	c.2037_2064del28	p.Leu680Glyfs*36 29	Exon 20	Indel	-	(Girot et al., 2019) 30
75	c.2037_2068delinsCTGG	p.Leu680Trpfs*36 29	Exon 20	Indel	-	(Lasseaux et al., 2018) 4,30
76	c.2056C>T	p.Gln686*	Exon 20	Nonsense	Pakistani	(Yousaf et al., 2016) 4

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

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

³The nomenclature of these HPS1 variants are included in this Table as reported, see reference for each specific variant for more details.

⁴At least one of the reported cases with this variant was identified by next generation sequencing.

⁵This variant likely leads to a loss of protein translation at the start codon of the longest splice variant of HPS1 (NM_000195.5). It is also predicted to affect splicing, as it is located at the exon 2–3 splice junction (Supplemental Table S2).

⁶NC_000010.11:g.10:98435762–98435882 (GRCh38): Genomic 121-bp deletion, including a part of intron 3 and exon 4 (Yousaf et al., 2016).

⁷Two unreported siblings from the NIH HPS cohort with this c.97_100delTCAG variant were of English-Irish-Scottish descent.

⁸Gray highlight: missense variant. See Supplemental Table S1 for pathogenicity predictions.

⁹novel = previously unreported variant detected in the NIH HPS cohort.

¹⁰This novel HPS1 variant was found heterozygous by next generation sequencing in 2 unreported siblings of Mexican descent from the HPS cohort. They were compound heterozygous for c.398+2T>C and c.1294_1298delATGGAinsT. This splice site variant is predicted to delete the splice junction of exon 18/intron 18 (Supplemental Table S2).

¹¹This variant was reported to result in skipping of exon 5 (Suzuki et al., 2004), and is a frequent variant in Japanese HPS patients (Ito et al., 2005).

¹²This variant occurs 3-bp from a splice junction and is predicted to affect the splice site (Supplemental Table S2). No experimental evidence is available (Khan et al., 2016). An alternative intronic splice site, inserting 43-bp of intron 6 sequence may be used as reported for variant c.507G>A occurring in the same codon (Merideth et al., 2009).

¹³This (silent) HPS1 variant p.Glu169Glu results in a splice defect (Merideth et al., 2009).

¹⁴This variant is reported to result in use of an alternative intronic splice donor site, 44-bp into intron 6, resulting in a frameshift of the coding region (Natsuga et al., 2005).

¹⁵In vitro studies showed that the HPS1 protein with this missense variant was unstable (Carmona-Rivera et al., 2013).

¹⁶This (missense) HPS1 variant occurs at the 3’ splice junction of exon 10, resulting in a cryptic intronic splice site and an aberrantly spliced mRNA that includes 144-bp intronic sequence, producing 11 novel amino acids followed by a stop codon (Carmona-Rivera, Hess, et al., 2011).

¹⁷This HPS1 frameshift variant occurs with a high prevalence in HPS-1 subjects of various ethnic backgrounds.

¹⁸This variant c.972dupC was reported as an ethnic founder variant in a small isolate in a Swiss village (Oh et al., 1998; Schallreuter et al., 1993)

¹⁹This variant was reported to result in in-frame skipping of exon 12 and removing 56 amino acids from the protein (Vincent et al., 2009).

²⁰This HPS1 variant was identified in one unreported subject of Canadian-German-Irish-Scottish-Swedish-Ukrainian descent from the NIH HPS cohort. This subject is compound heterozygous for c.1080C>G and c.1189delC.

²¹This HPS1 variant was identified in one unreported subject of Ukrainian descent from the NIH HPS cohort. This subject is compound heterozygous for c.1189delC and c.1228A>T.

²²This HPS1 variant was identified homozygous in one unreported subject of German descent from the NIH HPS cohort.

²³This HPS1 variant was identified in one unreported subject of German-English-Irish descent in the NIH HPS cohort. This subject is compound heterozygous for c.1189delC and c.1744–2A>C.

²⁴This HPS1 variant was found heterozygous in one unreported subject of English-Irish-Scottish in the NIH HPS cohort. This subject is compound heterozygous for c.1189delC and c.1937A>G.

²⁵This HPS1 16-bp duplication (c.1472_1487dup16-bp) is originates from a genetic isolate in northwest Puerto Rico (Oh et al., 1996; Santiago Borrero et al., 2006).

²⁶These 2 missense variants occur heterozygous on the same allele in two HPS siblings of our NIH cohort, their cells showed aberrant BLOC-3 assembly (Nazarian et al., 2008). Both missense variants are predicted to be deleterious to protein function (Supplemental Table S3). In vitro studies showed that the HPS1 protein with the p.Val547Leu variant was unstable and prevents proper BLOC-3 formation (Carmona-Rivera et al., 2013). No HPS1 coding/splice site variant was detected on the other allele, but this allele appeared to be subject to non-sense mediated mRNA decay (on cDNA analysis), indicating a likely (intronic) gene-truncation variant on this allele.

²⁷This HPS1 variant was identified in a subject with of Irish descent with HPS clinical features and accelerated pulmonary fibrosis. He was compound heterozygous for c.1744–2A>C (predicted to cause exon skipping (Oetting & King, 1999)) and c.1857+2T>C (predicted to result in use of alternative intronic splice site 4 base-pairs into intron 18, resulting in a frameshift of the coding region) (Supplemental Table S2) (McElvaney et al., 2018).

²⁸This HPS1 variant was identified homozygous by next generation sequencing in one unreported subject of Arabic descent in the NIH HPS cohort.

²⁹This HPS1 variant was found homozygous in one unreported subject of Dutch-French-German-Irish-Native American descent in the NIH HPS cohort. This novel splice site variant c.1858–1G>A, is predicted to create an alternative splice site 1-bp into exon 18, resulting in a frameshift of the coding region (Supplemental Table S2).

³⁰These Indels occur in the same region and result in a loss of the HPS1 termination codon (codon #701) and extension of the translated HPS1 protein.