Table 2 Molecular description of class 4 or 5 variants identified in this study.

From: Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD)

Gene

Nucleotide change

Protein change

Domain

Exon number

Variants classificationd

Allele frequency in gnomAD database

Number of probands in UMD or HGMD® databasese

Polyphen predictionf

SIFT predictiong

UMD-Predictor predictionh

SMAD3

c.363C>A

p.(Cys121*)

MH1

2

5

0

0

-

-

Path (100)

SMAD3

c.376C>T

p.(His126Tyr)

MH1

2

4

0

0

PossD (0.901)

D (0)

Path (96)

SMAD3

c.401–6G>Aa

p.(Val134Aspfs*33)

MH1

3

5

0

0

-

-

-

SMAD3

c.401_405dupb

p.(Pro136Phefs*52)

MH1

3

5

0

0

-

-

-

SMAD3

c.517C>T

p.(Gln173*)

Linker

3

5

0

0

-

-

Path (100)

SMAD3

c.545dup

p.(Gly183Trpfs*5)

Linker

4

5

0

0

-

-

-

SMAD3

c.701C>T

p.(Ser234Phe)

MH2

6

4

0

0

PD (1)

D (0.01)

Path (96)

SMAD3

c.715G>A

p.(Glu239Lys)

MH2

6

5

0

3

PD (1)

D (0)

Path (78)

SMAD3

c.736G>T

p.(Glu246*)

MH2

6

5

0

0

-

-

Path (100)

SMAD3

c.860G>A

p.(Arg287Gln)

MH2

6

5

0

0

PD (1)

D (0)

Path (93)

SMAD3

c.1117C>T

p.(Arg373Cys)

MH2

8

5

0

0

PD (1)

D (0)

Path (99)

SMAD3

c.1118G>A

p.(Arg373His)

MH2

8

4

0

0

PD (1)

D (0)

Path (81)

SMAD3

c.1189G>A

p.(Gly397Lys)

MH2

12

4

0

0

PD (0.987)

D (0)

Path (75)

FBN1

c.374A>G

p.(Asn125Ser)

EGF2

4

4

0

0

PD (0.97)

D (0)

Path (87)

FBN1

c.749G>A

p.(Cys250Tyr)

cbEGF1

7

5

0

0

PD (0.997)

D (0)

Path (100)

FBN1

c.1394G>T

p.(Cys465Phe)

EGF4

11

4

0

0

PD (0.986)

D (0)

Path (100)

FBN1

c.1453C>T

p.(Arg485Cys)

EGF4

11

5

0

3

PossD (0.719)

D (0)

Path (96)

FBN1

c.1925G>T

p.(Gly642Val)c

cbEGF6

15

4

1/246,214

0

PD (0.998)

D (0)

Path (93)

FBN1

c.3701G>C

p.(Arg1234Thr)

cbEGF15

29

4

0

0

PD (0.991)

D (0)

Path (99)

FBN1

c.4388A>G

p.(Asn1463Ser)c

cbEGF21

35

5

0

0

PD (0.989)

D (0)

Path (81)

FBN1

c.4892G>A

p.(Cys1631Tyr)

cbEGF23

39

5

0

0

PD (0.999)

D (0)

Path (100)

FBN1

c.5864A>G

p.(Gln1955Arg)

cbEGF29

47

5

0

0

B (0.121)

T (0.45)

Path (87)

FBN1

c.6998–13A>Ga

p.(Leu2332_Asp2333ins ValSerLeuPro)

TGFBP7

57

5

0

0

-

-

-

FBN1

c.7268G>A

p.(Gly2423Glu)c

cbEGF37

58

4

0

0

PD (1)

D (0)

Path (96)

FBN1

c.7754T>C

p.(Ile2585Thr)

cbEGF41

62

5

4/245,672

30

B (0.192)

D (0.01)

Path (93)

TGFBR1

c.673C>T

p.(Arg225Trp)

Protein kinase domain

4

4

1/245,312

0

PD (0.997)

D (0)

Path (100)

TGFBR1

c.688G>C

p.(Ala230Pro)

Protein kinase domain

4

4

0

0

PD (1)

D (0)

Path (84)

TGFBR1

c.984G>A

p.(Gly312Ser)

Protein kinase domain

5

4

1/245,820

1

PossD (0.842)

D (0)

Path (87)

TGFB2

c.346+1G>Cb

p.?

Latency-associated peptide

1

5

0

0

-

-

-

TGFB2

c.713G>A

p.(Trp238*)

Latency-associated peptide

4

5

0

0

-

-

Path (100)

TGFB2

c.1057G>T

p.(Asp353Tyr)

TGF-β 2

7

4

0

0

PD (0.999)

T (0.07)

Path (99)

TGFBR2

c.625C>T

p.(Leu209Phe)

Cytoplasmic domain

4

4

1/245,932

0

B (0.068)

T (0.52)

PPM (54)

TGFBR2

c.1609C>T

p.(Arg537His)

Cytoplasmic Protein kinase domain XI

7

4

0

0

PD (1)

D (0)

Path (96)

ACTA2

c.445C>T

p.(Arg149Cys)

ACTA2 chain

5

4

1/30,966

8

PD (0.958)

D (0)

Path (96)

ACTA2

c.952G>Ai

p.(Glu318Lys)

ACTA2 chain

8

4

0

0

PossD (0.902)

D (0)

Path (78)

MYLK

c.3196del

p.(Glu1066Asnfs*10)

Actin-binding domain

18

5

0

0

-

-

-

FLNA

c.7157–1G>Abj

p.?

Filamin repeat 22

45

5

0

0

-

-

-

FBN2

c.3980A>T

p.(Asn1327Ile)

cbEGF17

31

4

0

0

PossD (0.632)

D (0)

Path (100)

LOX

c.125G>A

p.(Trp42*)

Propeptide

1

5

0

0

-

-

Path (100)

MFAP5

c.62G>T

p.(Trp21Leu)

Peptide signal

3

4

10/277,056

0

PossD (0.657)

T (0.17)

PPM (51)

  1. In bold: variants found in two different probands in this study. aImpact on splicing confirmed by cDNA analysis; bSuspected impact on splicing (via Alamut Visual®); cFor the FBN1 gene, highly conserved residue involved in calcium binding; dAccording to ACMG-AMP guidelines15; eAccessible at http://www.umd.be/ and http://www.hgmd.cf.ac.uk/ac/index.php (consulted in August 2018); fHumVar prediction (score 0–1), B benign, PD  probably damaging, PossD possibly damaging; gScore 1–0, D deleterious, T tolerated; hScore 0–100, P polymorphism, Path pathogenic, P Path probably pathogenic, PPM probable polymorphism; iReported in this study in homozygous state; jreported in this study in heterozygous state in a female proband. When not specified, variants are in heterozygous state.
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