Table 1.
Mutation or VUS positive probands.
| # | Exon | Gene | cDNA base change | Predicted amino acid change | Type of mutation; domaina | Predictionb MutationTaster, PolyPhen-2 and Sift | Previously describedc | ExAC Frequency |
|---|---|---|---|---|---|---|---|---|
| MFS patients | ||||||||
| 2 | 14 | FBN1 | c.1709G > A | p.Cys570Tyr | Missense mutation; conserved cys in calcium-binding EGF-like#8 | P (0·999), P (0·997), P (0·002) | CM013918; UMD | / |
| 3 | 44 | FBN1 | c.5368C > T | p.Arg1790* | Nonsense mutation | P (1·000), NA, NA | CM054694; UMD | / |
| 25 | FBN1 | c.2956G > A | p.Ala986Thr | VUS | P (0·999), P (0·458), B (0·100) | UMD | 0·001508 | |
| 4 | Intron 51 | FBN1 | c.6313 + 3insT | / | Splice site mutation | NA | CS022105 | / |
| 5 | Intron 37 | FBN1 | c.4582 + 1G > T | / | Splice site mutation | NA | Novel | / |
| 6 | 64 | FBN1 | c.7828G > A | p.Glu2610Lys | Missense mutation, DIDE consensus sequenced | P (0·999), P (0·999), P (0·003) | CM972822; UMD | / |
| 7 | Intron 13 | FBN1 | c.1589–1G > A | / | Splice site mutation | NA | Novel | / |
| 8 | 10 | FBN1 | c.1090C > T | p.Arg364* | Nonsense mutation | P (1·000), NA, NA | CM032224; UMD | / |
| 9 | 55 | FBN1 | c.6629G > A | p.Cys2210Tyr | Missense mutation; conserved cys in calcium-binding EGF-like#38 | P (0·999), P (0·997), P (0·000) | Novel | / |
| 10 | 34 | FBN1 | c.4096G > A | p.Glu1366Lys | Missense mutation, DIDE consensus sequenced | P (0·999), P (0·995), P (0·980) | CM040037; UMD | / |
| 25 | FBN1 | c.2956G > A | p.Ala986Thr | VUS | P (0·999), P (0·458), B (0·100) | UMD | 0·001508 | |
| 12 | 49 | FBN1 | c.5947A > T | p.Lys1983* | Nonsense mutation | P (1·000), NA, NA | Novel | / |
| 13 | 38 | FBN1 | c.4621C > T | p.Arg1541* | Nonsense mutation | P (1·000), NA, NA | CM993159; UMD | / |
| 14 | 4 | FBN1 | c.254G > T | p.Cys85Phe | Missense mutation; conserved cys in EGF-like#1 | P (1·000), P (0·999), P (1·000) | Novel | / |
| 16 | 25 | FBN1 | c.2963G > A | p.Trp988* | Nonsense mutation | P (1·000), NA, NA | UMD | / |
| 17 | 32 | FBN1 | c.3845A > G | p.Asn1282Ser | Missense mutation, DIDE consensus sequenced | P (0·757), P (0·803), P (0·970) | CM972807; UMD | 0·0000742 |
| 9 | SMAD3 | c.1269T > G | p.Ser423Arg | VUS | P (0·999), P (0·980), P (0·002) | Novel | / | |
| 19 | 32 | FBN1 | c.3960T > A | p.Cys1320* | Nonsense mutation | P (1·000), NA, NA | CM054723; UMD | / |
| 20 | 63 | FBN1 | c.7712G > A | p.Cys2571Tyr | Missense mutation; conserved cys in calcium-binding EGF-like#45 | P (1·000), P (0·999), P (1·000) | Novel | / |
| 23 | 58 | FBN1 | c.7180C > T | p.Arg2394* | Nonsense mutation | P (1·000), NA, NA | CM993162; UMD | / |
| 24 | 22 | FBN1 | c.2639G > A | p.Gly880Asp | Missense mutation | P (1·000, P (1·000), P (1·000) | UMD | / |
| 25 | 35 | FBN1 | c.4222T > C | p.Cys1408Arg | Missense mutation; conserved cys in calcium-binding EGF-like#24 | P (1·000), P (0·999), P (1·000) | CM098517; UMD | / |
| 26 | 66 | FBN1 | c.8352_8353insT | p.Thr2785Tyrfs*16 | Frameshift mutation | NA | Novel | / |
| 27 | Intron 16 | FBN1 | c.1960 + 1G > A | / | Splice site mutation | NA | UMD | / |
| 34 | NOTCH1 | c.6413C > T | p.Pro2138Leu | VUS | P (0·999), P (0·494), B (0·599) | Novel | 0·000008763 | |
| 2 | FLNA | c.182G > A (A/–) | p.Ser61Asn | VUS | P (0·824), B (0·000), B (1·000) | Novel | / | |
| 28 | 64 | FBN1 | c.7831T > C | p.Cys2611Arg | Missense mutation; conserved cys in calcium-binding EGF-like#45 | P (1·000), P (0·998), P (1·000) | Novel | / |
| 29 | 4 | FBN1 | c.254G > A | p.Cys85Tyr | Missense mutation; conserved cys in EGF-like#1 | P (1·000), P (0·999), P (1·000) | Novel | / |
| MFS-like patients | ||||||||
| 1 | 4 | TGFBR1 | c.709A > G | p.Arg237Gly | VUS | P (0·999); P (0·997); P (0·002) | Novel | / |
| 11 | 63 | FBN1 | c.7754T > C | p.Ile2585Thr | Missense mutation | P (0·999), P (0·642), B (0·543) | CM972820; UMD | / |
| 15 | 61 | FBN1 | c.7549C > T | p.Gln2517* | Nonsense mutation | P (1·000), NA, NA | Novel | / |
| 18 | 58 | FBN1 | c.7039_7040delAT | p.Met2347 fs*19 | Frameshift mutation | NA | CD020234; UMD | / |
| 21 | 14 | FBN1 | c.1693C > T | p.Arg565* | Nonsense mutation | P (1·000), NA, NA | CM950438; UMD | / |
| 22 | 22 | FLNA | c.3421G > A (A/−) | p.Ala1141Thr | VUS | P (0·999), P (0·939), B (0·051) | Novel | 0·0003147 |
Nucleotide numbering uses +1 as the A of the ATG translation initiation codon in the reference sequence, with the initiation codon as codon 1. Patient numbers are in accordance with the patient numbers in Table 2.
/
: not present in ExAC B: benign; NA: not available; P: pathogenic.
a
Numbering of domains is based on Uniprot entry: P35555 (see Supplementary Table S1(a)–(c) for the relevant alignments).
b
dbSNFP, integrated into the VariantDB annotation tool (Vandeweyer et al., 2014), was used to automatically generate the prediction scores of MutationTaster, Polyphen-2 and SIFT respectively, as described by Liu et al., 2011.
c
In the UMD FBN1 (www.umd.be/FBN1/) or in the HGMD (public part: www.hgmd.cf.ac.uk/ac).
d
DIDE consensus sequence: Asp–Ile–Asp–Glu (see Supplementary Table S1(a)).