This table includes progranulin mutations considered pathogenic by the GENFI Genetics Panel. We regularly consider new mutations and if you would like us to include a new mutation in the table please email genfi@ucl.ac.uk along with the appropriate evidence.
Using plasma progranulin concentration as a measure of pathogenicity. The last column represents plasma progranulin concentrations measured using the Adipogen assay – actual values and accompanying notes can be found in this spreadsheet (mostly from this analysis by our team – Swift et al, 2024). If you would like to submit a plasma progranulin concentration to be included in this please email genfi@ucl.ac.uk. Note that we use the Adipogen assay mainly because it has been the most commonly used of the assays – others include commercial assays made by R+D and Biovendor, and academic-developed assays on the MSD platform. These assays are fairly well-correlated e.g. see data from an unpublished UCL study here but the actual concentrations differ (levels with the Adipogen assay being higher in general). The Adipogen assay has also undergone a validation study by the University of Gothenburg team; however, we do not know the particular antibodies or epitopes used in the Adipogen assay.
Why don’t we use CSF progranulin concentration? The calculated intrathecal fraction of progranulin is 80-90% i.e. progranulin found in CSF is largely not blood-derived [data from this paper]. CSF progranulin is therefore likely to be a better measure of pathogenicity of a mutation than plasma progranulin concentration. However, progranulin levels are 25-35 times lower on average in CSF compared to blood i.e. concentrations that are near to the lower limit of detection using most assays. Furthermore, very few patients have had their concentration measured in the literature – available measurements are in this spreadsheet, also mainly from Swift et al, 2024.
Why don’t we include GRN missense mutations? We have not included any GRN missense mutations in the table that are outside the signal peptide domain. The pathogenic nature of these are unclear and we treat these as variants of unknown significance within GENFI. However, both the C105Y and A199V variants have available plasma progranulin levels in mutation carriers that are only below the pathogenic cut-off, whilst other variants such as the C139R variant have plasma progranulin levels that are both below and above the cut-off. See the figure here. Missense GRN variants have been shown to be risk factors for Alzheimer’s disease (AD) and certainly there are reports of patients with such missense variants having AD pathology at post-mortem but no TDP-43 pathology (e.g. C139R).
| Mutation (NM_002087.2) | Predicted protein change | Mutation alias | Plasma progranulin |
|
|---|---|---|---|---|
| Complete gene | delGRN[DR184] | |||
| c.-9A>G | (-9A>G) | |||
| Intron 1 | c.-8+2T>G | IVS1+2T>G | ||
| Intron 1 | c.-8+3A>G | IVS1+3A>G | ||
| Intron 1 | c.-8+3A>T | IVS1+3A>T | ||
| Intron 1 | c.-8+5G>C | IVS1+5G>C | ||
| Intron 1-12 | delGRN[London] | |||
| Intron 1-12 | delGRN[French] |  |
||
| Intron 1-12 | delGRN[Tubingen] | |||
| Exon 1 | delGRN[exon 1] | |
||
| Exon 2 | c.1A>G | p.M1 | M1 (1A>G) | |
| Exon 2 | c.1A>T | p.M1 | M1 (1A>T) | |
| Exon 2 | c.2T>C | p.M1 | M1 (2T>C) | |
| Exon 2 | c.3G>A | p.M1 | M1 (3G>A) | |
| Exon 2 | c.6G>A | p.W2X | W2X | |
| Exon 2 | c.19T>G | p.W7G | W7G | |
| Exon 2 | c.19T>C | p.W7R | W7R | |
| Exon 2 | c.23T>A | p.V8E | V8E | |
| Exon 2 | c.25del | p.A9PfsX2 | A9fs | |
| Exon 2 | c.26C>A | p.A9D | A9D |  |
| Exon 2 | c.29T>C | p.L10S | L10S | |
| Exon 2 | c.58dup | p.C20LfsX45 | C20fs | |
| Exon 2 | c.63_64insC | p.D22RfsX43 | D22fs | |
| Exon 2 | c.70C>T | p.Q24X | Q24X | |
| Exon 2 | c.78C>A | p.C26X | C26X | |
| Exon 2 | c.80dup | p.V28CfsX37 | V28fs | |
| Exon 2 | c.87dup | p.C30LfsX35 | C30fs | |
| Exon 2 | c.87_90dup | p.C31LfsX35 | C31fs | |
| Exon 2 | c.102del | p.G35EfsX19 | G35fs | |
| Exon 2 | c.117dup | p.S40QfsX25 | S40fs | |
| Intron 2 | c.138+1G>A | IVS2+1G>A | |
|
| Intron 2 | c.138+1_138+3del | IVS2+1_+3del | ||
| Intron 2 | c.139-4C>T | IVS2-4C>T | ||
| Intron 2 | c.139del | p.D47TfsX7 | D47fs | |
| Exon 3 | c.146G>A | p.W49X | W49X (146G>A) | |
| Exon 3 | c.147G>A | p.W49X | W49X (147G>A) | |
| Exon 3 | c.154del | p.T52HfsX2 | T52fs |  |
| Exon 3 | c.232dup | p.S78FfsX41 | S78fs | |
| Exon 3 | c.234_235del | p.G79DfsX39 | G79fs | |
| Exon 3 | c.243del | p.S82VfsX174 | S82fs | |
| Exon 3 | c.255del | p.F86SfsX170 | F86fs | |
| Exon 3 | c.264G>A | EX3_ENDG>A | |
|
| Intron 3 | c.264+1G>A | IVS3+1G>A | ||
| Intron 3 | c.264+2T>C | IVS3+2T>C | |
|
| Intron 3 | c.265-7T>G | IVS3-7T>G | |
|
| Intron 3 | c.265-2del | IVS3-2del | |
|
| Exon 4 | c.280del | p.D94MfsX162 | D94fs | |
| Exon 4 | c.295_308del | p.Cys99fsX15 | C99fs | |
| Exon 4 | c.299del | p.P100HfsX156 | P100fs | |
| Exon 4 | c.314dup | p.C105WfsX14 | C105fs | |
| Exon 4 | c.328C>T | p.R110X | R110X | |
| Exon 4 | c.347C>A | p.S116X | S116X | |
| Exon 4 | c.349G>A | EX4_ENDG>A | |
|
| Intron 4 | c.349+1G>A | IVS4+1G>A | ||
| Intron 4 | c.349+1G>C | IVS4+1G>C | ||
| Intron 4 | c.349+2T>C | IVS4+2T>C | ||
| Intron 4 | c.350-1G>T | IVS4-1G>T | ||
| Exon 5 | c.350_462del | p.N118FfsX4 | N118fs | |
| Exon 5 | c.361del | p.V121WfsX135 | V121fs | |
| Exon 5 | c.373C>T | p.Q125X | Q125X | |
| Exon 5 | c.378C>A | p.C126X | C126X | |
| Exon 5 | c.380_381del | p.P127RfsX2 | P127fs | |
| Exon 5 | c.384_387del | p.Q130SfsX125 | Q130fs (384_387del) | |
| Exon 5 | c.385dup | p.S129KfsX? | S129fs | |
| Exon 5 | c.388C>T | p.Q130X | Q130X | |
| Exon 5 | c.388_391del | p.Q130SfsX125 | Q130fs (388_391del) | |
| Exon 5 | c.421_422del | p.V141YfsX18 | V141fs | |
| Exon 5 | c.443_444del | p.G148VfsX11 | G148fs | |
| Exon 5 | c.445_446del | p.C149fsX10 | C149fs | |
| Exon 5 | c.460C>T | p.Q154X | Q154X | |
| Intron 5 | c.462+1G>C | IVS5+1G>C | ||
| Intron 5 | c.463-1G>T | IVS5-1G>T | |
|
| Intron 5 | c.463_598del | p.A155WfsX56 | A155fs | |
| Exon 6 | c.468_474del | p.C157KfsX97 | C157fs | |
| Exon 6 | c.481_482del | p.R161GfsX36 | R161fs | |
| Exon 6 | c.472_496dup | p.P166LfsX2 | P166fs | |
| Exon 6 | c.512del | p.C171SfsX85 | C171fs | |
| Exon 6 | c.522_523insTGTGAAGACAGGGTGCACTGCTGTC | p.H175CfsX31 | H175fs | |
| Exon 6 | c.548del | p.G183fsAfsX73 | G183fs | |
| Exon 6 | c.559del | p.L187WfsX69 | L187fs (559del) | |
| Exon 6 | c.559dup | p.L187PfsX11 | L187fs (559dup) | |
| Exon 6 | c.560del | p.L187RfsX69 | L187fs (560del) | |
| Exon 6 | c.566dup | p.K190EfsX8 | K190fs | |
| Exon 6 | c.592_593del | p.R198GfsX19 | R198fs | |
| Intron 6 | c.598+1G>A | IVS6+1G>A | ||
| Intron 6 | c.599-2A>G | IVS6-2A>G | ||
| Intron 6 | c.599_708del | p.V200GfsX18 | V200fs | |
| Exon 7 | c.603dup | p.S203VfsX15 | S203fs (603dup) | |
| Exon 7 | c.607del | p.S203PfsX53 | S203fs (607del) | |
| Exon 7 | c.619dup | p.M207NfsX11 | M207fs | |
| Exon 7 | c.675_676del | p.S226WfsX28 | S226fs | |
| Exon 7 | c.687T>A | p.Y229X | Y229X | |
| Intron 7 | c.708+1G>A | IVS7+1G>A | |
|
| Intron 7 | c.708+1G>C | IVS7+1G>C | ||
| Intron 7 | c.708+4A>T | IVS7+4A>T | ||
| Intron 7 | c.708+5_708+8del | IVS7+5_+8del | |
|
| Intron 7 | c.708+6_708+9del | IVS7+6_+9del | |
|
| Intron 7 | c.709-3C>G | IVS7-3C>G | |
|
| Intron 7 | c.709-2A>G | IVS7-2A>G | |
|
| Intron 7 | c.709-2A>T | IVS7-2A>T | |
|
| Intron 7 | c.709-1G>A | IVS7-1G>A | |
|
| Intron 7 | c.709_835del | p.A237WfsX4 | A237fs | |
| Exon 8 | c.738C>A | p.C246X | C246X | |
| Exon 8 | c.745C>T | p.Q249X | Q249X | |
| Exon 8 | c.759_760del | p.C253X | C253X | |
| Exon 8 | c.759_760dup | p.D254VfsX3 | D254fs | |
| Exon 8 | c.761_762insTG | p.L255AfsX2 | L255fs | |
| Exon 8 | c.768_769dup | p.Q257PfsX27 | Q257fs (768_769dup) | |
| Exon 8 | c.769del | p.Q257RfsX26 | Q257fs (769del) | |
| Exon 8 | c.775_778del | p.K259AfsX23 | K259fs | |
| Exon 8 | c.775A>T | p.K259X | K259X | |
| Exon 8 | c.776dup | p.C260VfsX14 | C260fs | |
| Exon 8 | c.813_816del | p.T272SfsX10 | T272fs | |
| Exon 8 | c.833_834del | p.T278SfsX7 | T278fs | |
| Exon 8 | c.834dup | p.V279SfsX7 | V279fs | |
| Intron 8 | c.835_835+1insCTGA | IVS8_+1insCTGA | |
|
| Intron 8 | c.835+1G>A | IVS8+1G>A | ||
| Intron 8 | c.836-2A>C | IVS8-2A>C | |
|
| Intron 8 | c.836-1G>C | IVS8-1G>C | ||
| Intron 8 | c.836-1G>T | IVS8-1G>T | ||
| Exon 9 | c.848_854dup | p.D285EfsX3 | D285fs | |
| Exon 9 | c.882T>G | p.Y294X | Y294X | |
| Exon 9 | c.888_889del | p.C296WfsX20 | C296fs | |
| Exon 9 | c.898C>T | p.Q300X | Q300X | |
| Exon 9 | c.900_901dup | p.S301CfsX61 | S301fs | |
| Exon 9 | c.903_904insTG | p.G302WfsX60 | G302fs | |
| Exon 9 | c.907dup | p.A303GfsX14 | A303fs (907dup) | |
| Exon 9 | c.907del | p.A303PfsX58 | A303fs (907del) | |
| Exon 9 | c.909del | p.W304GfsX57 | W304fs (909del) | |
| Exon 9 | c.910_911insTG | p.W304LfsX58 | W304fs (910_911insTG) | |
| Exon 9 | c.911G>A | p.W304X | W304X (911) | |
| Exon 9 | c.912G>A | p.W304X | W304X (912) | |
| Exon 9 | c.918C>A | p.C306X | C306X | |
| Intron 9 | c.933+1del | IVS9+1del | ||
| Intron 9 | c.933+1G>A | IVS9+1G>A | |
|
| Exon 10 | c.942C>A | p.C314X | C314X | |
| Exon 10 | c.945_946del | p.C315X | C315X | |
| Exon 10 | c.975del | p.F326LfsX35 | F326fs | |
| Exon 10 | c.985_986insAC | p.D329?fsX? | D329fs | |
| Exon 10 | c.988_989del | p.T330AfsX6 | T330fs | |
| Exon 10 | c.988_989dup | p.Q331RfsX31 | Q331fs | |
| Exon 10 | c.998del | p.G333VfsX28 | G333fs | |
| Exon 10 | c.1009C>T | p.Q337X | Q337X | |
| Exon 10 | c.1010_1011del | p.Q337RfsX39 | Q337fs | |
| Exon 10 | c.1013_1024del | p.Q337_340del | Q337_340del | |
| Exon 10 | c.1012_1013delGGinsC | p.G338RfsX23 | G338fs | |
| Exon 10 | c.1014del | p.H340TfsX21 | H340fs | |
| Exon 10 | c.1021C>T | p.Q341X | Q341X | |
| Exon 10 | c.1031G>A | p.W344X | W344X | |
| Exon 10 | c.1048dup | p.A350GfsX18 | A350fs | |
| Exon 10 | c.1070del | p.P357HfsX4 | P357fs | |
| Exon 10 | c.1072C>T | p.Q358X | Q358X | |
| Exon 10 | c.1095_1096del | p.C366X | C366X | |
| Exon 10 | c.1144dup | p.T382NfsX32 | T382fs (1144dup) | |
| Exon 10 | c.1145del | p.T382SfsX30 | T382fs (1145del) | |
| Exon 10 | c.1157G>A | p.W386X | W386X | |
| Exon 10 | c.1160dup | p.C388LfsX26 | C388fs | |
| Exon 10 | c.1179del | p.A394LfsX18 | A394fs | |
| Exon 10 | c.1179G>A | EX10_ENDG>A | ||
| Intron 10 | c.1179+1del | IVS10+1del | ||
| Intron 10 | c.1179+2T>C | IVS10+2T>C | ||
| Intron 10 | c.1179+3A>T | IVS10+3A>T | |
|
| Intron 10 | c.1179+3A>G | IVS10+3A>G | |
|
| Intron 10 | c.1179+104_1536delinsCTGA | IVS10+104_1536delinsCTGA | ||
| Exon 11 | c.1184_1187del | V395fs | ||
| Exon 11 | c.1196_1197del | p.D399AfsX14 | D399fs | |
| Exon 11 | c.1201C>T | p.Q401X | Q401X | |
| Exon 11 | c.1212C>A | p.C404X | C404X | |
| Exon 11 | c.1216C>T | p.Q406X | Q406X | |
| Exon 11 | c.1231_1232del | p.V411SfsX2 | V411fs | |
| Exon 11 | c.1231_1232dup | p.A412X | A412X | |
| Exon 11 | c.1243C>T | p.Q415X | Q415X | |
| Exon 11 | c.1246dup | p.C416LfsX30 | C416fs | |
| Exon 11 | c.1252C>T | p.R418X | R418X | |
| Exon 11 | c.1256_1263dup | p.I422EfsX72 | I422fs | |
| Exon 11 | c.1263_1264insGAAGCGAG | p.E421?fsX? | E421fs | |
| Exon 11 | c.1292_1302dup | p.S435PfsX60 | S435fs | |
| Exon 11 | c.1317_1318del | p.P439?fsX? | P439fs | |
| Exon 11 | p.D441HfsX4 | D441fs | ||
| Exon 11 | c.1336C>T | p.Q446X | Q446X | |
| Exon 11 | c.1354del | p.V452WfsX39 | V452fs | |
| Exon 11 | c.1359dup | p.Q454AfsX58 | Q454fs | |
| Exon 11 | c.1392G>A | p.W464X | W464X | |
| Exon 11 | c.1395dup | p.C466LfsX46 | C466fs | |
| Exon 11 | c.1402C>T | p.Q468X | Q468X | |
| Intron 11 | c.1414-1G>A | IVS11-1G>A | |
|
| Intron 11 | c.1415_1645del | p.A472_Q548del | A472_Q548del | |
| Exon 12 | c.1414_1644del | p.A472VfsX10 | A472fs | |
| Exon 12 | c.1420_1421del | p.C474LfsX37 | C474fs | |
| Exon 12 | c.1428_1431del | p.E476DfsX14 | E476fs | |
| Exon 12 | c.1446C>A | p.C482X | C482X | |
| Exon 12 | c.1477C>T | p.R493X | R493X | |
| Exon 12 | c.1492G>T | p.E498X | E498X | |
| Exon 12 | c.1494_1498del | p.E498DfsX12 | E498fs | |
| Exon 12 | c.1507C>T | p.Q503X | Q503X | |
| Exon 12 | c.1508del | p.Q503RfsX14 | Q503fs | |
| Exon 12 | c.1535del | p.P512LfsX5 | P512fs | |
| Exon 12 | c.1538_1539del | p.H513RfsX16 | H513fs | |
| Exon 12 | c.1603C>T | p.R535X | R535X | |
| Exon 12 | c.1612C>T | p.R538X | R538X |