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Table 1 SACS mutations

From: Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): expanding the genetic, clinical and imaging spectrum

Family No.

Nucleotide change1

Amino acid change

Mutation type

Exon

Allele frequency in 1846 controls

dbSNP

EVS

PhyloP2[-14,1;6,4]

Grantham distance3[0–215]

In-silico predictions4

Novel variant

Pathogenicity class5

Patients with 2 pathogenic or likely pathogenic SACS variants

            

#1 index

c.9305_9306insT

p.Leu3102Phefs*8

frame shift

10

0

-

-

NA

NA

NA

yes

Pathogenic (class 5)

 

c.9305_9306insT

p.Leu3102Phefs*8

          

#1 sister

see above

           

#2

c.2182C>T

p.Arg728*

nonsense

9

0

-

-

ND

NA

NA

no6

Pathogenic (class 5)

 

c.13056delT

p.Phe4352Leufs*11

frame shift

10

0

-

-

NA

NA

NA

yes

Pathogenic (class 5)

#3 index

c.3769G>T

p.Gly1257*

nonsense

10

0

-

-

ND

NA

NA

yes

Pathogenic (class 5)

 

c. 8584A>T

p.Lys2862*

nonsense

10

0

-

-

ND

NA

NA

yes

Pathogenic (class 5)

#3 sister

see above

           

#4 index

c.11542_11544del

p.Ile3848del

in-frame deletion

10

0

-

-

NA

NA

NA

yes

Likely pathogenic (VUS class 4)

 

c.11542_11544del

p.Ile3848del

          

#4 brother

see above

           

#5 index

c.2387delT

p.Leu796Tyrfs*13

frame shift

10

0

-

-

NA

NA

NA

yes

Pathogenic (class 5)

 

c.11984_11986 dupTGT

p.L3995dup

in-frame duplication

10

0

-

-

NA

NA

NA

yes

Likely pathogenic (VUS class 4)

#5 sister

see above

           

#6

c.11624 G>A

p.Arg3875His

missense

10

0

-

-

6.34

29

Deleterious

yes

Likely pathogenic (VUS class 4)

 

c.1647_1658del

p.Leu549_Leu552del

In-frame deletion

8

0

-

-

NA

NA

NA

yes

Likely pathogenic (VUS class 4)

 

c.13538 G>A

p.Ser4513Asn

missense

10

0

rs138328181 (0% ESP Cohort pop)

0.02% (EA), 0% (AA)

3.43

46

Contradictory

yes

Uncertain (VUS class 3)

#7

c.5544dupA

p.Val1849Serfs*48

frame shift

10

0

-

-

NA

NA

NA

yes

Pathogenic (class 5)

 

c.12603C>A

p.Tyr4201*

nonsense

10

0

-

-

ND

NA

NA

yes

Pathogenic (class 5)

#8

c.7277 G>C

p.Arg2426Pro

missense

10

0

-

-

5.69

103

Deleterious

yes

Likely pathogenic (VUS class 4)

 

c.8920_8923dup

p.Tyr2975Phefs*29

frame shift

10

0

-

-

NA

NA

NA

yes

Pathogenic (class 5)

#9

c.4954C>T

p.Gln1652*

nonsense

10

0

-

-

ND

NA

NA

yes

Pathogenic (class 5)

 

c.5125C>T

p.Gln1709*

nonsense

10

0

-

-

ND

NA

NA

no6

Pathogenic (class 5)

Patients with 2 SACS variants of uncertain clinical significance class 3 (VUS3)

            

#10

c.1373C>T

p.Thr458Ile

missense

8

14/3500

rs61729954 (0.3% ESP Cohort pop; 3.1% AGI ASP pop)

0.33% (EA); 0.05% (AA)

6.26

89

Deleterious

yes

Uncertain (VUS class 3)

 

c.1373C>T

p.Thr458Ile

          

#11

c.1373C>T (see patient #10)

p.Thr458Ile

missense

8

14/3500

rs61729954 (0.3% ESP Cohort pop; 3.1% AGI ASP pop)

0.33% (EA); 0.05% (AA)

6.26

89

Deleterious

yes

Uncertain (VUS class 3)

 

c.2983 G>T

p.Val995Phe

missense

10

11/3500

rs142967124 (0.1% ESP Cohort pop)

0.24% (EA); 0.02% (AA)

-0.2

50

Contradictory

yes

Uncertain (VUS class 3)

  1. EA= European alleles; AA= African American alleles; NA = not applicable; ND = not determined; rs = reference single nucleotide polymorphism (SNP) identifier; VUS = variant of uncertain clinical significance. 1 Nomenclature of sequence variants follows the recommendations by the Human Genome Variation Society (HGVS, http://www.hgvs.org/mutnomen/) and refers to the cDNA sequence NM_014363.4. 2 PhyloP was used as a conservation score as originally implemented by Pollard and colleagues. It allows the rating of nucleotides from “not conserved” (-14.1) to “highly conserved” (6.4) [13]. 3 The Grantham distance was used to evaluate physico-chemical differences of amino acids (0 = no physico-chemical differences; 215 = large differences) [14]. 4 In-silico predictions were performed using PolyPhen-2 [9], SIFT [10] and MutationTaster [11]5 Classification of novel sequence variants is according to [7]. 6 Reported in [6].
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Orphanet Journal of Rare Diseases

ISSN: 1750-1172