Number of Index Patients 1 Variant Data 2 Exon DNA Change Protein Change dbSNP ID gnomAD MAF (v. 2.1.1) ACMG Interpretation ClinVar Interpretation ClinVar ID References 1 1 1i-15i c.68-366_2312-791del P 0 6 2 p.Cys27Trp rs2228671 VUS P/LP 226304 1 1 2 c.85A > T p.Arg29Ter rs879254401 P P 251011 0 6 2 c.97C > T p.Gln33Ter rs121908024 0.000007963 P P 3683 0 6 3 c.191_313del p.Leu64_Pro105delinsSer P 0 5 3 c.193_202delTCTGTCACCTinsGGACTTCA p.Ser65Glyfs * 64 LP 1 1 3 c.193T > A p.Ser65Thr VUS 0 5 3 c.195dupT p.Val66Cysfs * 64 rs879254435 P P 251075 2 4 3 c.200C > T p.Thr67Ile rs1337448484 0.00001060 VUS VUS 629411 2 1 3 c.203G > T p.Cys68Phe VUS 2 2 3 c.230dup p.Arg78ProfsTer55 rs879254440 P P 251083 1 4 3 c.241C > T p.Arg81Cys rs730882078 0.000007953 VUS P/LP/VUS 183083 0 6 3 c.245G > C p.Cys82Ser VUS VUS 431509 1 4 3 c.246C > A p.Cys82Ter rs875989891 P P 226309 0 6 3 c.285C > A p.Cys95Ter rs139400379 P P 251115 0 6 3i c.313 + 1G > A rs112029328 0.00002784 P P/LP 3736 0 5 3i c.313 + 2T > G LP 1 3 4-8 c.317-1185dup p.Pro106_Val395dup LP 2 4 4 c.326G > A p.Cys109Tyr rs121908042 0.000003996 LP P/LP 226319 2 4 4 c.343C > T p.Arg115Cys rs774723292 0.00002792 LP P/LP/VUS 251162 1 4 4 c.347G > A p.Cys116Tyr LP 0 6 4 c.347_349delGCC p.Cys116_His117delinsTyr rs879254483 LP LP 251164 1 1 4 c.351_352insTTCC p.Asp118PhefsTer13 P 1 5 4 c.355_356insTTCC p.Gly119ValfsTer12 P 1 4 4 c.420G > C p.Glu140Asp rs879254520 LP P/LP 251216 0 5 4 c.444T > G p.Cys148Trp rs879254528 LP LP 251228 0 6 4 c.451G > C p.Ala151Pro rs763233960 0.00001195 LP VUS 251234 6 2 4 c.478T > G p.Cys160Gly rs879254540 LP LP 251248 0 6 4 c.499T > C p.Cys167Arg rs879254547 LP P/LP 251255 1 4 4 c.502G > C p.Asp168His rs200727689 LP P/LP 251258 1 4 4 c.519C > G p.Cys173Trp rs769318035 0.000007958 LP P/LP 251277 0 6 4 c.530C > T p.Ser177Leu rs121908026 0.00001592 LP P/LP 3686 1 3 4 c.534T > G p.Asp178Glu rs879254566 LP P/LP 251287 0 6 4 c.542C > T p.Pro181Leu rs557344672 0.000007958 LP LP 431512 2 4 4 c.551G > A p.Cys184Tyr rs121908039 0.00009554 LP P/LP 3739 2 1 4 c.587C > G p.Pro196Arg VUS 0 6 4 c.618T > G p.Ser206Arg rs879254595 LP P/LP 251325 5 3 4 c.622G > A p.Glu208Lys rs879254597 LP P/LP 251328 0 6 4 c.626G > A p.Cys209Tyr rs879254600 LP P/LP 251332 5 3 4 c.654_656delTGG p.Gly219del rs121908027 P P/LP 226329 1 3 4 c.658_663delCCCGAC p.Pro220_Asp221del rs1555803409 LP P 440589 0 5 4-6 Del 5 kb incl. ex. 4-6 LP 3 4 4 c.666C > A p.Cys222Ter rs756613387 0.000004005 P P 251364 1 4 4 c.672_686delCAAATCTGACGAGGA p.Asp224_Glu228del rs1555803439 LP LP 441189 0 5 4 c.670_671insG p.Asp224GlyfsTer4 rs879254629 P P 251372 1 1 4 c.670_678dup p.Asp224_Ser226dup LP 3 4 4 c.682G > A p.Glu228Lys rs121908029 0.00001614 LP P/LP 3691 0 6 4 c.682G > T p.Glu228Ter rs121908029 0.00001074 P P/LP 226333 1 4 4 c.693C > A p.Cys231Ter rs121908035 P P/LP 3730 0 5 5 p.Glu240Ter * LP 0 6 5 p.Glu240Lys * VUS P/LP/VUS 200920 1 4 5 c.768C > A p.Asp256Glu rs879254671 VUS LP 438322 0 6 5 p.Cys261Phe * VUS LP 3740 0 6 5 c.796G > A p.Asp266Asn rs875989907 0.00001193 LP P/LP 226334 3 4 5 c.798T > A p.Asp266Glu rs139043155 0.00003535 VUS P/LP/VUS 161287 2 3 5 c.810C > A p.Cys270Ter rs773328511 P P 251465 1 4 6 c.825_826delCT p.Cys276ArgfsTer24 rs879254691 P P 251478 2 4 6 c.829G > A p.Glu277Lys rs148698650 0.0005056 VUS/LB P/VUS/LB/B 183097 0 6 6 p.Glu288Lys VUS P/LP/VUS 161268 2 4 6 c.905G > T p.Cys302Phe rs879254715 LP P 430768 0 6 6 c.922G > A p.Glu308Lys rs879254721 VUS LP 251528 0 6 6 c.925_931delCCCATCA p.Pro309LysfsTer59 rs387906304 P P 3729 1 1 6 c.921T > A p.Asp307Glu VUS 1 1 6 c.935A > G p.Glu312Gly rs1380197577 0.000003984 VUS 0 5 6 c.939_940 + 3delCGGTG p.Cys313AspfsTer17 rs879254727 P P 251536 3 3 6i c.940 + 3_940 + 6del VUS P/VUS 869390 0 5 5i_6i c.817 + 303_940 + 943del p.Val273_Cys313del VUS 1 4 6i c.941-3C > G VUS 1 4 6i c.941-2A > G rs112366278 P P/LP 251554 1 4 7 c.949G > A p.Glu317Lys rs746834464 0.00005311 VUS P/LP 251567 2 1 7 c.954C > G p.Cys318Trp VUS 1 1 7 c.970G > T p.Gly324Cys VUS 1 4 7 c.974G > A p.Cys325Tyr rs879254746 VUS P/LP 251580 1 1 7 c.976T > C p.Ser326Pro VUS 8 3 7 c.986G > A p.Cys329Tyr rs761954844 0.00002479 VUS P/LP/LB 226344 0 6 7 c.1009G > A p.Glu337Lys rs539080792 0.0000935 VUS VUS 523729 0 6 7 rs755757866 NA (G > A)\0.000007967 (G > T) LP (G > A)\NA (G > T) 251600 (G > A)\NA (G > T) 1 4 7 c.1027G > A p.Gly343Ser rs730882096 0.00002832 VUS P/LP/VUS 183106 1 4 7 c.1048C > T p.Arg350Ter rs769737896 0.000007977 P P 226342 1 3 7 c.1054T > C p.Cys352Arg rs879254769 VUS LP 251618 3 4 7i c.1061-8T > C rs72658861 0.005498 VUS/LB VUS/PB/B 36451 3 1 8 c.1123T > G p.Tyr375Asp VUS 1 1 8 c.1129_1130insT p.Cys377LeufsTer1 LP 1 4 8 c.1162del p.His388ThrfsTer25 P P 226348 1 1 8 c.1168A > G p.Lys390Glu VUS 1 1 8 c.1183delG p.V395fs LP 1 4 8i c.1186 + 1G > T rs730880131 P P 180403 1 1 8i-10i c.1186 + 568_1586 + 1067del LP 3 4 8i c.1187-10G > A rs765696008 0.00002798 VUS P/LP 226349 1 1 8i c.1187-7C > G VUS 28 3 9 c.1202T > A p.Leu401His rs121908038 VUS P/LP 3735 2 4 9 c.1217G > A p.Arg406Gln rs552422789 0.00001593 VUS P/LP/VUS 228798 5 3 9 c.1222G > A p.Glu408Lys rs137943601 0.000007965 LP P/LP 36453 0 5 9 p.Arg410Gly * VUS 0 5 9 p.Met412Val * VUS 4 3 9 c.1246C > T p.Arg416Trp rs570942190 0.00002389 LP P/LP 183110 1 3 9 c.1252G > T p.Glu418Ter rs869320651 P P 251755 0 5 9 p.Glu418Gly * VUS 0 6 9 c.1277T > C p.Leu426Pro rs879254851 VUS P/LB 251763 1 4 9 c.1285G > A p.Val429Met rs28942078 0.00001194 LP P/LP 3694 0 5 9 c.1291_1331del41 p.Ala431Ter rs879254854 LP 1 4 9 c.1292C > T p.Ala431Val VUS 0 6 9 p.Leu432Arg * VUS 0 5 9 p.Asp433Glu * rs778309692 0.000003980 VUS 0 6 9 p.Asp433His * VUS 0 6 9 p.Asp433Tyr * VUS 0 6 9 c.1302delG p.Glu435MetfsTer15 P 1 4 9 c.1322T > A p.Ile441Asn rs879254862 VUS LP 251782 2 2 9 c.1327T > C p.Trp443Arg rs773566855 0.000003980 LP 0 6 9 c.1328G > A p.Trp443Ter rs879254866 P P 251789 0 6 9 c.1340C > G p.Ser447Cys rs879254870 VUS LP 251797 0 6 9i c.1358 + 1G > A rs775924858 P P/LP 251802 1 1 10 c.1444G > T p.Asp482Tyr rs139624145 LP LP 251845 1 2 10 c.1465T > A p.Tyr489Asn VUS 1 4 10 c.1471A > G p.Thr491Ala VUS 1 4 10 c.1474G > A p.Asp492Asn rs373646964 0.00002386 VUS P/LP/VUS 161285 1 4 10 c.1502C > T p.Ala501Val rs755667663 0.000007954 LP P/LP 251874 0 6 10 c.1532T > C p.Leu511Ser rs879254932 VUS LP 251887 1 4 10 c.1561G > A p.Ala521Thr rs879254940 VUS VUS 251898 1 4 10 c.1577C > A p.Pro526His rs879254944 VUS VUS 496019 1 4 10i c.1586 + 5G > A rs781362878 0.00003189 VUS LP/VUS 251909 1 1 11 c.1618delG p.Ala540ProfsTer8 LP 1 3 11 c.1633G > A p.Gly545Arg rs879254965 LP P/LP 251942 0 6 11 p.Gly549Asp * rs28941776 0.00002386 VUS P/LP 3698 0 5 11 c.1655_1672del LP 1 4 11 c.1672G > T p.Glu558Ter rs879254980 P P 251964 0 5 11 p.Glu558Lys * VUS 0 5 11 c.1686_1693delGCCCAATGinsT p.Trp562CysfsTer5 rs879254984 P P 251968 1 1 11 c.1693G > A p.Gly565Ser rs1344561983 0.000003978 VUS 4 1 11 c.1696A > T p.Ile566Phe VUS 1 1 11 c.1705 + 3delA VUS 0 6 11 p.Leu568Va l * VUS 1 4 12 c.1706-10G > A rs17248882 0.002220 VUS/LB VUS/LB/B 226368 1 4 12 c.1708_1710delCTC p.Leu571del rs772492150 0.000007953 VUS 1 4 12 c.1729T > C p.Trp577Arg rs879255000 LP P/LP 252001 0 5 12 c.1741A > C p.Lys581Gln VUS 2 4 12 c.1747C > T p.His583Tyr rs730882109 0.0001025 VUS P/LP 200921 1 4 12 c.1750T > C p.Ser584Pro rs879255010 VUS LP/VUS 252015 2 2 12 c.1756T > C p.Ser586Pro VUS 1 1 12 c.1774G > T p.Gly592Trp VUS 29 3 12 c.1775G > A p.Gly592Glu rs137929307 0.00005656 LP P/LP 161271 2 4 12 c.1784G > A p.Arg595Gln rs201102492 0.00003889 VUS P/LP/VUS 183126 0 5 12 p.Leu605Val * VUS 0 5 12 p.Leu605Arg * VUS 0 5 12 p.Ala612Gly * VUS 1 2 12i c.1846-3T > G VUS 0 5 13 c.1855-1856insA p.Phe619TyrfsTer26 rs879255053 P P 252082 0 6 13 c.1859G > C p.Trp620Ser VUS 1 3 13 c.1864G > A p.Asp622Asn rs879255059 LP LP 252092 1 1 13 c.1898delG p.Arg633fs VUS 2 4 13 c.1898G > A p.Arg633His rs754536745 0.00002121 VUS P/LP/VUS 226380 0 5 13 c.1936C > A p.Leu646Ile rs779940524 0.000003977 VUS LP 252118 1 4 13 c.1945C > T p.Pro649Ser rs879255080 VUS LP 252121 3 4 13 c.1955T > C p.Met652Thr rs875989936 0.000003977 VUS LP/VUS 226382 1 4 13 c.1966C > A p.His656Asn rs762815611 LP B/LP/VUS 252136 1 4 14 c.1998G > A p.Trp666Ter rs752935814 P P 252161 0 5 14 c.1999T > A p.Cys667Ser rs150021927 VUS LP 252162 1 4 14 c.2001_2002delTG p.Cys667_Glu668delinsTer rs1600743301 LP P 630543 1 4 14 c.2043C > A p.Cys681Ter rs121908031 0.000007959 P P/LP 3699 3 4 14 c.2089G > C p.Ala697Pro rs776217028 VUS LP 252213 0 6 14i-16i c.2141-966_2390-330del p.Glu714_Ile796del LP 1 1 14i-15i c.2141-799_2311 + 689del LP 1 1 15 c.2189A > C p.Lys730Thr VUS 0 5 15 c.2191delG p.Val731SerfsTer6 rs879255161 P P 252253 0 6 15 c.2215C > T p.Gln739Ter rs370018159 P P/LP 252258 1 4 15 c.2230C > T p.Arg744Ter rs200793488 0.000003979 LP P 430795 0 6 15 c.2231G > A p.Arg744Gln rs137853963 0.0008030 VUS LP/VUS/LB/B 68104 1 1 15 c.2244_2245insG p.Thr749AspfsTer33 VUS 1 1 15i-17i c.2312-2107_2547 + 620del LP 1 1 16 c.2324T > C p.Val775Ala rs780300776 0.00002121 VUS LB/VUS 440691 0 5 16 c.2326G > T p.Ala776Ser VUS 1 1 16 c.2327C > T p.Ala776Val VUS 1 4 16 c.2347A > C p.Lys783Gln rs769318961 0.000007954 VUS 1 1 16 c.2374del p.Ile792LeufsTer137 LP 3 3 16 c.2389G > A p.Val797Met rs750518671 0.000007957 VUS P/LP/VUS 226393 1 4 16 c.2389G > C p.Val797Leu rs750518671 VUS VUS 565983 1 4 16 c.2389 + 2T > G rs879255188 P LP 252302 4 3 16i c.2389 + 5G > C rs879255191 VUS VUS 661713 2 4 16 c.2389 + 5G > A rs879255191 VUS P/LB 252306 1 1 17 c.2390T > A p.Val797Glu VUS 2 4 17 c.2416_2417insG p.Val806fs P P/LP 252330 0 6 17 c.2416dupG p.Val806GlyfsTer11 rs773618064 P P/LP 252330 1 1 17 c.2429G > A p.Trp810Ter LP 1 4 17 c.2448G > C p.Lys816Asn rs1399689294 0.00003186 VUS LP/VUS 440698 1 4 17 c.2473A > G p.Asn825Asp rs879255215 VUS LP 252340 1 3 17 c.2479G > A p.Val827Ile rs137853964 0.0009193 VUS/LB LP/VUS/LB/B 36462 1 4 17 c.2531G > A p.Gly844Asp rs121908037 VUS LP 3734

PV-negative (n = 1) PV-positive (n = 6) Any PV-positive (n = 6) Heterozygous PV (n = 4) Homozygous PV (n = 2) c.682G > T (p.E228X) (n = 2) CNV, exon 8-12 (n = 1) c.519C > G (C173W) (n = 1) G558X andc.-136C > T (n = 1) c.1567G > A (V523M) and c.-136C > T (n = 1) Pre-evolocuamb LDL-C, mg/dL 157 154 (135, 327) 169 126 138 138 410 299 Post-evolocuamb LDL-C, mg/dL 27 103 (61, 194) 149 99 107 33 329 70 LDL-C reduction, % 82.8 21.9 (17.8, 76.2) 11.8 21.4 22.5 76.1 19.8 76.6 LDL-C reduction, % of expected value 153.3 46.0 (32.4, 141.1) 27.5 39.7 52.2 140.9 34.0 141.8

Gene Genomic coordinate Nucleotide change* Mutation type Amino acid change Affected patients (frequency) LDLR chr19:11213417 c.268G>A Missense p.D90N 1 (0.014) LDLR chr19:11216000 c.418G>A Missense p.E140K 1 (0.014) LDLR chr19:11216101 c.519C>G Missense p.C173W 1 (0.014) LDLR chr19:11216243 c.661G>A Missense p.D221N 1 (0.014) LDLR chr19:11216264 c.682G>T Nonsense p.E228X 3 (0.043) LDLR chr19:11216264 c.682G>A Missense p.E228K 1 (0.014) LDLR chr19:11217315 c.769C>T Missense p.R257W 1 (0.014) LDLR chr19:11227594 c.1765G>A Missense p.D589N LDLR chr19:11224013 c. 1246C>T Missense p.R416W 1 (0.014) LDLR chr19:11226885 c.1702C>G Missense p.L568V 1 (0.014) LDLR chr19:11231112 c. 2054C>T Missense p.P685L 2 (0.028) LDLR chr19:11221326 c.941-2A>G Splicing, acceptor site (exon6-2nt) Frameshift 1 (0.014) LDLR chr19:11222188 c.1061-2A>G Splicing, acceptor site (exon7-2nt) Frameshift 1 (0.014) APOB chr2:21229160 c.10580C>T Missense p.R3527Q 2 (0.028) PCSK9 chr1:55505604 c.94G>A Missense p.E32K 1 (0.014)