Overview of the Mutational and Phenotypic Spectrum of Hereditary Leiomyomatosis and Renal

Supplementary data:

Reference Number Number of Reference Nucleotide Protein of of families with of Mutation Consequence functional families RCC description study Whole gene 1 / [6, 7, 38] deletion Whole gene 1 / [6, 7, 38] deletion Whole gene 1 / [6, 7, 38] deletion Whole gene 1 / [38] deletion 1 DelExon1 / 1 [19] 1 DupExon7 / [16] 1 IVS3+1delG Splice Site [12] 1 IVS4+1G>A Splice Site [12] 2 c.10C>T p.Gln4X [6, 13]

1 c.28G>T p.Glu10X [38] 1 c.49delC p.Leu17fs [6]

1 c.104del p.Asn35fs 1 [38] 1 c.111insA p.Lys37X 1 [4] 1 c.138+1G>C Splice Site 1 [4] [14] 8 c.172C>T p.Arg58X 4 [4, 6, 24] [14] 2 c.173G>C p.Arg58Pro 1 [10] 7 c.191A>C p.Asn64Thr [4, 6] [9] 1 c.220G>C p.Ala74Pro [6] [9] 1 c.266T>C p.Leu89Ser 1 [4] [14] 1 c.275A>G p.His92Arg [39] 1 c.288delG p.Val97X [3] 1 c.305G>C p.Ser102X 1 [4] [14] 1 c.346G>T p.Ser115Ile [8] 1 c.349A>G p.Arg117Gly [4] 1 c.410A>G p.His137Arg [6] [9] 1 c.424C>T p.Gln142X [8] 1 c.425A>G p.Gln142Lys [12] 1 c.425A>G p.Gln142Arg [6] [9] 1 c.431C>T p.Ser144Leu [3] 1 c.434A>G p.Asn145Ser [3] 1 c.446A>G p.Pro149Leu [39] 1 c.455T>C p.Met152Thr [3] 3 c.458A>G p.His153Arg 1 [1] 2 c.542_543delAG p.Glu181fs 2 [6] 1 c.557T>C p.Ile186Thr [7] [9] 1 c.3bpdel p.Ile186fs [6] 3 c.560A>G p.Lys187Arg [6, 7, 39] [9] 1 c.559_561delAAG p.Lys187fs [6] 1 c.566del p.Gly189Aspfs [37] 2 c.568C>T p.Arg190Cys 1 [4, 39] [14] 1 c.569G>T p.Arg190Leu [3] [3, 4, 6, 7, 21 c.569G>A p.Arg190His 3 [9] 22, 38, 39] 1 c.695G>A p.Gly232Glu [38] 1 c.716G>T p.Gly239Val [6] [9] 1 c.780_781delGC p.Leu260fs [3] [14] 1 c.782_788del7bp p.Pro261fs [3, 11] [14] 1 c.799A>T p.Asn267Lys [9]

2 c.823C>T p.His275Tyr 1 [3, 38] 1 c.836T>A p.Val279Asp [3] 1 c.859A>C p.Thr287Pro [13] 1 c.869G>A p.Cys290Lys [18] 1 c.873T>G p.Ser291Arg [38] 1 c.875T>C p.Leu292Pro [3] 2 c.891T>A p.Asn297Asp [3, 4] [14] 1 c.898C>T p.Arg300X 1 [6] 4 c.905-1G>A Splice Site [39] 2 c.934G>A p.Glu312Lys [7] [9] 1 c.1081_1083del4bp p.Asn318fs [8] 1 c.954T>A p.Asn318Lys 1 [7] 2 c.964A>G p.Ser322Gly [3, 4] 2 c.968G>A p.Ser323Asn [3, 7] 1 c.989A>G p.Asn330Ser 1 [17] 1 c.1002T>G p.Ser334Arg [20] 1 c.1004ins2bp p.Glu335fs 1 [3]

1 c.1015A>G p.Met339Val [38] 1 c.1025C>A p.Ala342Asp [4] 1 c.1051G>C p.Val351Leu [8] [7, 20, 24, 8 c.1060G>A p.Gly354Arg [9] 38] 1 c.1081G>T p.Glu361X [38] 1 c.1103T>C p.Met368Thr [20]

1 c.1105del p.Met369X [38] 1 c.1126T>A p.Ser376Pro 1 [4] [14] 1 c.1162delA p.Thr388Fs 1 [3]

1 c.1187A>C p.Gln396Pro 1 [4] [14] 1 c.1218delG p.Ile406fs [9] 1 c.1210G>T p.Glu404X [12] 1 c.1238delA p.Ile413fs [12] 2 c.1265A>G p.Lys422Cys [3] [14] 1 c.1271A>G p.Lys424Arg [15] [15] c.1300- 1 p.Ser437fs [3] 1307del8bpdup 1 c.1328C>A p.Ala443Asp 1 [23] 1 c.1339delG p.Gly447fs 1 [3] 1 c.1340delG p.Gly447fs [14] [14] 1 c.1346-1347delTC p.Leu449fs [14] [14] 1 c.1391T>C p.Leu464Pro [7] [9]

Supplementary Table S1. List of the FH germline mutations described in the literature. RCC: renal cell cancer.

FH Nucleotide Protein Familial First Family Age enzymatic Phenotype mutation mutation status description activity PRCCII at 34 years old (first proband 36 41.30* considered as sporadic) + one F41 c.220G>C p.Ala74Pro small cutaneous leiomyoma [6, 9] father 64 45.65* No clinical manifestation PRCCII at 34 years old + proband 34 49.16 cutaneous leiomyomas F11 c.250-2A>G SP (deceased) This report father 56 52.38 Two renal cysts

PRCCII at 52 years old + proband 53 57.2 c.247_249+1 cutaneous leiomyomas F10 SP This report delGAGGinsA sister 42 52.13 No clinical manifestation

Sarcomatoid RCC + uterine proband 52 51.79 leiomyomas (deceased) F35 c.1060G>A p.Gly354Arg [7, 9] One very small cutaneous mother 76 54.7 leiomyoma

Supplementary Table S2. FH enzymatic activity (% compared to WT) in patients from same families but with different phenotypes. The FH activity was determined on lymphoblastoid cell line or (*) on peripheral blood lymphocytes.