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. 2013 Mar 15;8:41. doi: 10.1186/1750-1172-8-41

Table 1.

SACS mutations

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)

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].