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

Supplementary data:

Number of families / Nucleotide Mutation / Protein Consequence / Number of families with RCC / Reference of description / Reference of functional study
1 / Whole gene deletion / / / [6, 7, 38]
1 / Whole gene deletion / / / [6, 7, 38]
1 / Whole gene deletion / / / [6, 7, 38]
1 / Whole gene deletion / / / [38]
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]
21 / c.569G>A / p.Arg190His / 3 / [3, 4, 6, 7, 22, 38, 39] / [9]
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]
8 / c.1060G>A / p.Gly354Arg / [7, 20, 24, 38] / [9]
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]
1 / c.1162delA / p.Thr388Fs / 1 / [3] / [14]
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]
1 / c.1300-1307del8bpdup / p.Ser437fs / [3]
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.

Family / Nucleotide mutation / Protein mutation / Familial status / Age / FH enzymatic activity / Phenotype / First description
F41 / c.220G>C / p.Ala74Pro / proband / 36 / 41.30* / PRCCII at 34 years old (first considered as sporadic) + one small cutaneous leiomyoma / [6, 9]
father / 64 / 45.65* / No clinical manifestation
F11 / c.250-2A>G / SP / proband / 34 / 49.16 / PRCCII at 34 years old + cutaneous leiomyomas (deceased) / This report
father / 56 / 52.38 / Two renal cysts
F10 / c.247_249+1 delGAGGinsA / SP / proband / 53 / 57.2 / PRCCII at 52 years old + cutaneous leiomyomas / This report
sister / 42 / 52.13 / No clinical manifestation
F35 / c.1060G>A / p.Gly354Arg / proband / 52 / 51.79 / Sarcomatoid RCC + uterine leiomyomas (deceased) / [7, 9]
mother / 76 / 54.7 / One very small cutaneous 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.