Table 2.

Rare, predicted deleterious KLK1 and GGCX variants among 2572 PAH cases. Participants were heterozygous for the indicated variants

Participant ID	Gender	Age at dx (years)	PAH subclass	Ancestry	Gene**	Nucleotide change	Amino acid change	Variant type	MAF (ExAC)	CADD score	Revel score
08–022	F	60	IPAH	EUR	KLK1	c.46+1G>T	p.(=)	Splicing	–	24	–
10–096	F	68	IPAH	EUR	KLK1	c.60dup	p.Ile21Aspfs*12	Frameshift	4.29E−05	–	–
28–049	F	36	APAH-CHD	EUR	KLK1	c.60dup	p.Ile21Aspfs*12	Frameshift	4.29E−05	–	–
06–058	M	13	IPAH	EUR	KLK1	c.70C>T	p.Arg24Trp	D-Mis	8.47E−06	26	0.56
13–002	F	71	IPAH	EUR	KLK1	c.70C>T	p.Arg24Trp	D-Mis	8.47E−06	26	0.56
06–007	M	26	IPAH	EUR	KLK1	c.113G>A	p.Trp38*	Stop-gain	8.30E−06	35	–
12–061	F	51	IPAH	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
14–018	M	61	IPAH	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
17–075	F	82	APAH-CTD	EUR	KLK1	c.469G>A	p.Gly157Ser	D-Mis	9.36E−05	29	0.72
18–026	F	37	IPAH	EUR	KLK1	c.644G>A	p.Gly215Glu	D-Mis	–	30	0.85
19–013	F	51	IPAH	EUR	KLK1	c.650C>T	p.Pro217Leu	D-Mis	2.52E−05	29	0.60
19–033	F	37	IPAH	EUR	KLK1	c.689G>C	p.Trp230Ser	D-Mis	8.26E−06	25	0.50
06–014	M	35	FPAH	EUR	GGCX	c.137C>G	p.Ser46Cys	D-Mis	5.77E−05	23	0.70
04–020	F	36	IPAH	EUR	GGCX	c.G203G>C	p.Arg68Pro	D-Mis	–	35	0.96
12–207	F	43	IPAH	EUR	GGCX	c.G203G>C	p.Arg68Pro	D-Mis	–	35	0.96
32–003	M	81	IPAH	EUR	GGCX	c.248G>A	p.Arg83Gln	D-Mis	–	34	0.92
32–008	F	36	IPAH	AFR	GGCX	c.322C>T	p.Arg108Cys	D-Mis	1.65E−05	31	0.55
08–013	F	66	APAH-CTD	EUR	GGCX	c.646_647delinsCA	p.Val216Gln	In-frame	–	31	***
26–036	F	52	IPAH	EUR	GGCX	c.722 T>C	p.Phe241Ser	D-Mis	–	33	0.94
30–031	F	55	IPAH	EUR	GGCX	c.722 T>C	p.Phe241Ser	D-Mis	–	33	0.94
04–029	F	60	IPAH	EUR	GGCX	c.734 T>A	p.Leu245*	Stop-gain	–	40	–
04–087	F	54	IPAH	EUR	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
34–005	M	66	IPAH	EUR	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
11–004	F	24	IPAH	HIS	GGCX	c.763G>A	p.Val255Met	D-Mis	1.65E−05	34	0.86
22–108	F	40	APAH-HIV	AFR	GGCX	c.899C>T	p.Ser300Phe	D-Mis	2.53E−05	28	0.82
28–110	F	56	IPAH	AFR	GGCX	c.899C>T	p.Ser300Phe	D-Mis	2.53E−05	28	0.82
28–096	F	23	IPAH	EUR	GGCX	c.938_939del	p.Pro313Argfs*33	Frameshift	1.00E−04	–	–
08–046	F	53	APAH-Porto	EUR	GGCX	c.950G>A	p.Arg317Gln	D-Mis	1.67E−05	33	0.81
12–205	F	55	IPAH	EUR	GGCX	c.1017_1018insT	p.Ser340*	Stop-gain	–	–	–
15–008	F	14	APAH-CHD	EUR	GGCX	c.1075C>T	p.Arg359Cys	D-Mis	–	28	0.76
21–037	F	45	APAH-CTD	AFR	GGCX	c.1128C>G	p.Phe376Leu	D-Mis	–	27	0.85
06–039	F	28	IPAH	EUR	GGCX	c.1224C>A	p.His408Gln	D-Mis	8.24E−06	23	0.75
37–004	F	48	IPAH	EUR	GGCX	c.1249G>A	p.Asp417Asn	D-Mis	1.65E−05	26	0.72
30–034	F	49	APAH-CTD	HIS	GGCX	c.1304G>A	p.Arg435Gln	D-Mis	8.24E−06	29	0.67
14–029	M	48	IPAH	EUR	GGCX	c.1306C>T	p.Arg436*	Stop-gain	3.30E−05	41	–
37–010	F	77	APAH-CTD	EUR	GGCX	c.1306C>T	p.Arg436*	Stop-gain	3.30E−05	41	–
11–090	F	47	APAH	AFR	GGCX	c.1465G>A	p.Val489Met	D-Mis	2.47E−05	26	0.68
05–013	M	63	APAH-Porto	HIS	GGCX	c.1480 T>G	p.Ser494Ala	D-Mis	–	26	0.84
28–033	F	51	IPAH	EUR	GGCX	c.1758C>G	p.Tyr586*	Stop-gain	–	45	–
17–033	F	74	APAH-CTD	AFR	GGCX	c.1772C>T	p.Thr591Met	D-Mis	3.30E−05	29	0.83

*Rare, deleterious variants defined as gnomAD AF ≤ 1.00E−04 and REVEL > 0.5

**KLK1 transcript NM_002257.3 and GGCX transcript NM_000821.6

***REVEL score could not be computed for this 2-nt substitution because machine learning is based on 1-nt substitutions. Inclusion in the table was based on REVEL > 0.9 for single nt substitution and PROVEAN = deleterious for 2-nt substitution