Supplementary Table S1.

Patient Variants Included in Functional Studies

Variant	Frequency1	Reference	Pathogenicity predictions
			REVEL	CADD	Rhapsody
p.Val2Phe	0.00005	(Bal et al., 2019)	0.15	25.2	0.16
p.Leu21Pro	0.00003	(Ellingford et al., 2016)	0.93	25.8	0.59
p.Leu27Pro	0.001	(Marrakchi et al., 2011)	0.60	24.3	0.67
p.His32Arg	-	(Körber et al., 2013)	0.15	21.4	0.06
p.Lys35Arg	0.001	(Setta-Kaffetzi et al., 2013)	0.42	23.3	0.39
p.Ile42Asn	0.000009	(Takeichi etal., 2017)	0.74	26.4	0.84
p.Val44Met	0.00006	(Wang et al., 2016)	0.17	18.7	0.32
p.Arg48Trp	0.001	(Onoufriadis et al., 2011)	0.63	25.6	0.65
p.Pro76Leu	0.005	(Körber et al., 2013)	0.58	23.0	0.72
p.Pro82Leu	0.004	(Li et al., 2014)	0.03	22.2	0.13
p.Arg102Trp	0.005	(Setta-Kaffetzi et al., 2013)	0.58	23.1	0.33
p.Arg102Gln	0.000009	(Li et al., 2013)	0.42	25.1	0.40
p.Arg103Gln	0.00009	(Mössner et al., 2018)	0.09	22.2	0.11
p.Glu112Lys	0.00006	(Hayashi et al., 2014)	0.78	27.0	0.43
p.Ser113Leu	0.007	(Onoufriadis et al., 2011)	0.32	22.8	0.62
p.Thr123Arg	-	(Farooq et al., 2013)	0.62	23.5	0.69
p.Thr123Met	0.0001	(Kanazawa et al., 2013)	0.58	23.4	0.70

The recurrent p.Leu27Pro and p.Ser113Leu mutations are highlighted in bold font.

Abbreviation: CADD, Combined Annotation Dependent Depletion; REVEL, Rare Exome Variant Ensemble Learner.

¹Maximum frequency observed across gnomAD (r2.1.1) populations.