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Table 5 Presumably neutral missense variants

From: Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

Gene Nucleotide change Exon Amino acid change Frequency in
USH alleles
(×/108)
Frequency in
control alleles
References
MYO7A       
  47T>C 3 L16S >10   [58]
  905G>A 9 R302H 2 1/494 [78]
  4996A>T 36 S1666C >10   U39226
  5156A>G 37 Y1719C* 3 2/306 [91]
  5860C>A 43 L1954I >10   U39226
USH1C       
  2192G>A 21 R731Q 1   This study
  2457G>C 24 E819D >10   [92]
CDH23       
  7C>T 1 R3C >10   [55]
  1469G>C 14 G490A >10   [55]
  1487G>A 14 S496N >10   [55]
  3625A>G 30 T1209A* 1 5/486 [55]
  3664G>A 30 A1222T 4   [55]
  4051G>A 31 D1351N >10   [55]
  4310G>A 34 R1437Q 6   [55]
  4723A>G 37 T1575A >10   [55]
  4858G>A 38 V1620M 1 2/306 [55]
  5023G>A 38 V1675I >10   [55]
  5411G>A 41 R1804Q >10   [55]
  5418C>G 41 D1806E 2   [93]
  5692G>A 42 A1898T 1 0/306 This study
  5996C>G 45 T1999S >10   [55]
  6130G>A 46 E2044K >10   [55]
  6197G>A 46 R2066Q 1 0/306 [55]
  6329C>T 47 A2110V 1   This study
  6596T>A 47 I2199N 1 0/306 This study
  6809G>A 48 R2270H 1   This study
  6847G>A 49 V2283I 6   [55]
  6869C>T 49 T2290M 1 0/306 This study
  7073G>A 50 R2358Q >10   [55]
  7139C>T 50 P2380L >10   [55]
  7762G>C 54 E2588Q 1 1/306 [55]
  9049G>A 61 D3017N 1   This study
  9373T>C 65 F3125L 1 7/306 [56]
  9949G>A 69 A3317T 1 1/306 This study
PCDH15       
  55T>G 2 S19A >10   [94]
  1039C>T 10 L347F 1 3/666 This study
  1138G>A 11 G380S >10   This study
  1304A>C 11 D435A >10   AL834134
  1910A>G 15 N637S 2   [92]
  2786G>A 21 R929Q >10   AL834134
  4850A>G 34§ N1617S 2   This study
  4853A>C 36§ E1618A >10   This study
  4982A>C 37§ Q1661P >10   This study
USH2A       
  373G>A 2 A125T >10   [95]
  1434G>C 8 E478D 3   [95]
  1663C>G 10 L555V* 1 0/306 [96]
  1931A>T 11 D644V >10   [95]
  4457G>A 21 R1486K >10   AF055580
  4994T>C 25 I1665T >10   [89]
  6317T>C 32 I2106T >10   [89]
  6506T>C 34 I2169T >10   [89]
  6713A>C 35 E2238A 6 5/306 [89]
  6875G>A 36 R2292H 4   [28]
  8624G>A 43 R2875Q 4   [89]
  8656C>T 43 L2886F 4   [89]
  9008T>C 45 V3003A 1   This study
  9262G>A 47 E3088K* 1 3/306 [28]
  9296A>G 47 N3099S 4   [89]
  9343A>G 47 T3115A 3 5/306 [28]
  9430G>A 48 D3144N 4   [89]
  9595A>G 49 N3199D 6   [28]
  10232A>C 52 E3411A >10   [89]
  11504C>T 59 T3835I >10   [28]
  11602A>G 60 M3868V >10   [89]
  11677C>A 60 P3893T* 1 1/306 [28]
  15091C>T 70 R5031W 2 2/306 [28]
  15377T>C 71 I5126T* 3 2/306 [87]
VLGR1       
  365C>T 4 S122L >10   This study
  P194H 6 P194H 1 5/468 This study
  1033C>A 7 Q345K 1   This study
  2261T>C 12 V754A 1 0/306 This study
  3289G>A 17 G1097S 1 3/478 This study
  3482C>G 19 S1161C 1 0/306 This study
  4939A>G 23 I1647V >10   This study
  5780C>T 28 T1927M >10   [11]
  5851G>A 28 V1951I >10   [11]
  5953A>G 28 N1985D >10   [11]
  5960C>T 28 P1987L >10   [11]
  6012G>T 28 L2004F >10   [11]
  6695A>G 30 Y2232C >10   [11]
  7034A>G 32 N2345S >10   [11]
  7582C>T 33 P2528S 1 1/306 This study
  7751A>G 33 N2584S >10   [97]
  8291C>T 36 S2764L 6   [11]
  8407G>A 37 A2803T 4   [11]
  9280G>A 43 V3094I >10   This study
  9743G>A 45 G3248D >10   [11]
  9650C>T 45 A3217V 2   [11]
  10411G>A 49 E3471K >10   [97]
  10429G>T 50 D3477Y 1   This study
  10490A>G 50 Q3497R 1   This study
  10577T>C 51 M3526T 3   This study
  10936T>C 52 S3646P 3   This study
  11599G>A 56 E3867K >10   This study
  12269C>A 59 T4090N 2   This study
  14029T>C 69 F4677L 1 2/478 This study
  14905T>C 73 W4969R 2   This study
  17626G>A 82 V5876I >10   This study
  18475A>G 88 M6159V 2   This study
WHRN       
  229A>T 1 T77S 1 1/468 [98]
  979C>A 4 L327I 1   This study
  1318G>A 6 A440T >10   [99]
  1838T>C 9 M613T >10   This study
  2348T>C 10 V783A >10   [99]
  2388C>A 10 N796K >10   [99]
  1. Novel mutations are in bold. * Mutations considered pathogenic by prediction Software, but excluded by segregation studies. § Exons 34, 36 and 37 are specific to isoforms CD1, CD2 and CD3, respectively.
  2. The pathogenicity of several exonic variants found in our patients and predicted to be pathogenic in previous studies and/or by prediction software was further investigated. The p.T1209A missense mutation in CDH23 has previously been reported in two affected families and considered as pathogenic [55, 58]. However, we found it in five of 486 control alleles from French and Maghreban populations. The p.Y1719C missense mutation in MYO7A seems to represent a frequent sequence variant in the Moroccan population, with an estimated carrier frequency of 0.07 [100], and was observed in three out of 306 control alleles. The p.R302H mutation in MYO7A, which affects a residue within a non-conserved region of the motor domain, was detected in one out of 494 control alleles. Moreover, two of five different MYO7A cDNA clones isolated from three independent libraries were found to encode a histidine residue at codon position 302 [101], which further argues in favor of a non-pathogenic sequence variant. The p.E3088K missense mutation in USH2A, previously described by Dreyer et al., was present in three out of 306 control alleles, which argues in favor of a non-pathogenic sequence variant [26, 28]. The missense mutation p.I5126T in USH2A has been reported as likely pathogenic [87]. We found it in two USH1 patients, who in addition carried two pathogenic mutations in MYO7A. We detected it in two individuals from the French control population, suggesting that it is a non-pathogenic sequence variant. The p.L555V mutation in USH2A has been found in homozygous state in one Spanish patient, together with a biallelic splice site variant (c.1841-2A>G) [26]. Numerous, presumably neutral, isocoding and intronic variants were also observed (listed in Additional file 2Table S1).