Table 3.
Potentially Pathogenic Variants Identified in the adRP Cohort
| Mutation |
Families (n) | Scores |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Type Variant | Protein | Nucleotide | Seg. | Prior | Struct. | SIFT | Funct | PolyP. | Gran. | Comment | |
| CA4—carbonic anhydrase 4 | |||||||||||
| Pathogenic | None | ||||||||||
| Probably pathogenic | None | ||||||||||
| Benign | Thr198Met | 593 C→T | 1 | No | No | - | No | - | Possib. | 81 | .96/.04 in African control subjects |
| Val234Ile | 700 G→A | 1 | No | No | - | No | - | Benign | 29 | In one control | |
| Val237Leu | 709 G→T | 1 | No | No | - | No | - | Benign | 32 | .98/.02 in African control subjects | |
| Arg239Gln | 716 G→A | 1 | No | No | - | No | - | Benign | 43 | .95/.05 in African control subjects | |
| CRX—cone rod homeobox protein | |||||||||||
| Pathogenic | Arg41Gln | 122 G→A | 1 | 5 | Yes38,44 | - | Yes | - | Prob. | 43 | |
| Leu146_Pro149del | 436_447del | 1 | 15 | Yes38 | - | NA | - | NA | NA | ||
| Probably pathogenic | None | ||||||||||
| Benign | None | ||||||||||
| FSCN2—retinal fascin | |||||||||||
| Pathogenic | None | ||||||||||
| Probably pathogenic | None | ||||||||||
| Benign | Val17Ile | 49 G→A | 1 | No | No | - | No | - | Benign | 29 | In one white control subjects |
| Gly165Arg | 493 G→A | 1 | No | No | - | No | - | Benign | 125 | ||
| Pro231Ser | 691 C→T | 1 | No | No | - | No | - | Benign | 74 | ||
| Ala323Thr | 967 G→A | 1 | No | Yes45 | - | Yes | - | Possib. | 58 | .96/.04 in white control subjects | |
| Leu489Val | 1465 C→G | 1 | No | No | - | No | - | Benign | 32 | .98/.02 in white control subjects | |
| IMPDH1 (RP10)—inosine monophosphate dehydrogenase | |||||||||||
| Pathogenic | Asp226Asn | 676 G→A | 5 | 20+ | Yes9 | - | Yes | Yes | Prob. | 23 | Affects CBS domain9 |
| Probably pathogenic | None | ||||||||||
| Benign | None | ||||||||||
| NRL—neural retinal leucine zipper | |||||||||||
| Pathogenic | None | ||||||||||
| Probably pathogenic | None | ||||||||||
| Benign | Arg147Arg | 441 G→A | 2 | Prbn. | No | - | - | - | - | - | Silent substitution |
| Gln174Arg | 521 A→G | 1 | No | No | - | Yes | - | Prob. | 43 | ||
| PRPF3 (RP18)—pre-mRNA splicing factor 3 | |||||||||||
| Pathogenic | Pro493Ser | 1477 C→T | 1 | Prbn. | Yes15 | - | Yes | - | Prob. | 74 | |
| Thr494Met | 1481 C→T | 1 | Prbn. | Yes15 | - | Yes | - | Prob. | 81 | ||
| Probably pathogenic | None | ||||||||||
| Benign | None | ||||||||||
| PRPF8 (RP13)—pre-mRNA splicing factor 8 | |||||||||||
| Pathogenic | Phe2304Leu | 6912 C→G | 1 | 2 | Yes17 | - | Yes | - | Prob. | 22 | |
| Arg2310Gly | 6928 A→G | 1 | 2 | Yes17 | - | Yes | - | Prob. | 125 | ||
| Glu2331fs/ter 2358 | 6991delG | 2 | 2 | No | fs | NA | NA | NA | NA | ||
| Probably pathogenic | IVS 41/exon 42 junction | IVS41-4 G→A | 1 | Prbn. | No | as | NA | NA | NA | NA | |
| Ala2328Val | 6983 C→T | 1 | Prbn. | No | - | No | - | Benign | 64 | ||
| Benign | None | ||||||||||
| PRPF31 (RP11)—pre-mRNA splicing factor 31 | |||||||||||
| Pathogenic | Exon 2/IVS 2 junction | IVS2+1 G→A | 1 | Prbn. | No | as | NA | NA | NA | NA | |
| Gln74ter | 220 C→T | 1 | Prbn. | No | ps | NA | NA | NA | NA | ||
| Asn131fs/ter197 | 390delC | 1 | 3 | No | fs | NA | NA | NA | NA | ||
| Glu141ter | 421 G→T | 1 | Prbn. | No | ps | NA | NA | NA | NA | ||
| Met212fs/ter238 | 636delG | 1 | 2 | No | fs | NA | NA | NA | NA | ||
| Gly253fs/ter317 | 758_767del | 1 | Prbn. | No | fs | NA | NA | NA | NA | ||
| Exon 10/IVS 10 junction | 1049_IVS10+20del/insCCCCT | 1 | Prbn. | No | as | NA | NA | NA | NA | ||
| Exon 10/IVS 10 junction | IVS10+1 G→A | 1 | 5 | No | as | NA | NA | NA | NA | ||
| Glu325ter | 973 G→T | 1 | Prbn. | No | ps | NA | NA | NA | NA | ||
| Probably pathogenic | Ala291Pro | 871 G→C | 1 | Prbn. | No | - | NA | NA | Possib. | 27 | |
| Cys299Arg | 895 T→C | 1 | 4 | No | - | NA | NA | Prob. | 180 | 1 Nonpenetrant if pathogenic | |
| Benign | Gly272Val | 815 G→T | 1 | No | No | - | NA | NA | Prob. | 109 | Chinese variant |
| RDS—peripherin 2 | |||||||||||
| Pathogenic | Val206_Val209del | 616_627del | 1 | 4 | No | Yes | NA | NA | NA | NA | 4 Amino acids lost |
| Exon 2/IVS 2 junction | IVS2+3 A→T | 4 | 20+ | Yes3 | as | NA | NA | NA | NA | Was “1068+3 A→T” | |
| Arg46ter | 136 C→T | 1 | Prbn. | Yes46 | ps | NA | NA | NA | NA | ||
| Leu126Arg | 377 T→G | 1 | Prbn. | Yes* | - | Yes | - | Prob. | 102 | ||
| Arg172Gln | 516 G→T | 1 | Prbn. | Yes47 | - | No | - | Benign | 91 | ||
| Digenic Leu185Pro | 554 T→C | 1 | 3 | Yes48 | - | Yes | - | Prob. | 98 | Digenic with ROM1 Ala114fs | |
| Pro210Arg | 629 C→G | 1 | Prbn. | Yes49 | - | Yes | - | Prob. | 103 | ||
| Pro210Leu | 629 C→T | 1 | Prbn. | Yes50 | - | Yes | - | Prob. | 98 | ||
| Pro216Ser | 646 C→T | 1 | Prbn. | Yes51 | - | Yes | - | Prob. | 74 | ||
| Pro216Leu | 647 C→T | 2 | 6 | Yes18 | - | Yes | - | Prob. | 98 | ||
| Gly266Asp | 797 G→A | 2 | 7 | Yes* | - | Yes | Yes | Possib. | 94 | Transmembrane site | |
| Probably pathogenic | Tyr141Cys | 422 A→G | 1 | 4 | No | - | Yes | - | Prob. | 149 | Other mutation at 141 |
| Ser198Arg | 594 C→G | 1 | Prbn. | No | - | Yes | - | Prob. | 110 | ||
| Pro216Arg | 647 C→G | 1 | Prbn. | No | - | Yes | - | Prob. | 103 | Other mutations at 216 | |
| Benign | Gly137Ser | 409 G→A | 1 | No | No | - | No | - | Benign | 56 | Family has another pathogenic mutation |
| Leu45Phe | 133 C→T | 1 | No | Yes35 | - | Yes | - | Possib. | 22 | Common Caribbean variant | |
| RHO-rhodopsin | |||||||||||
| Pathogenic | Thr17Met | 50 C→T | 1 | Prbn. | Yes52 | - | Yes | - | Prob. | 81 | |
| Pro23His | 68 C→A | 20 | 20+ | Yes53 | - | Yes | - | Prob. | 77 | ||
| Leu57Arg | 170 C→T | 1 | Prbn. | Yes54 | - | Yes | Yes | Possib. | 102 | Transmembrane site | |
| Thr58Arg | 173 C→G | 1 | Prbn. | Yes55 | - | Yes | Yes | Possib. | 71 | Transmembrane site | |
| Gly106Arg | 318 G→A | 1 | 8 | Yes54 | - | Yes | - | Prob. | 125 | ||
| Gly106Trp | 316 G→T | 2 | 2 | Yes56 | - | Yes | - | Prob. | 184 | ||
| Cys110Phe | 329 G→T | 1 | Prbn. | Yes57 | - | Yes | Yes | Prob. | 205 | Disulfide bond | |
| Arg135Trp | 403 C→T | 4 | 8 | Yes56 | - | Yes | Prob. | - | 101 | ||
| Arg135Leu | 404 G→T 405 G→T | 3 | 20+ | Yes56 | - | Yes | Prob. | - | 102 | ||
| Ala164Val | 491 C→T | 1 | Prbn. | Yes57 | - | Yes | Yes | Benign | 64 | Transmembrane site | |
| Pro170Arg | 509 C→G | 1 | 7 | Yes3 | - | Yes | Yes | Possib. | 103 | Transmembrane site | |
| Pro171Ser | 511 C→T | 1 | Prbn. | Yes58 | - | Yes | Yes | Possib. | 74 | Transmembrane site | |
| Pro171Gln | 512 C→A | 1 | Prbn. | Yes59 | - | Yes | Yes | Possib. | 76 | Transmembrane site | |
| Glu181Lys | 541 G→A | 1 | Prbn. | Yes55 | - | Yes | Prob. | Prob. | 56 | ||
| Cys187Tyr | 560 G→A | 1 | 3 | Yes60 | - | Yes | Yes | Prob. | 194 | Disulfide bond | |
| Asp190Asn | 568 G→A | 2 | 2 | Yes61 | - | No | No | Benign | 23 | ||
| His211Arg | 632 A→G | 1 | Prbn. | Yes62 | - | Yes | Yes | Possib. | 29 | Transmembrane site | |
| Pro267Leu | 800 C→T | 1 | Prbn. | Yes52 | - | Yes | Yes | Possib. | 98 | Transmembrane site | |
| IVS 4/exon 5 junction | IVS4-1 G→A | 1 | 7 | Yes63 | as | NA | NA | NA | NA | ||
| Val345Met | 1033 G→A | 1 | Prbn. | Yes† | - | Yes | Yes | Prob. | 21 | BNG binding site | |
| Pro347Ala | 1039 C→G | 1 | Prbn. | Yes62 | - | Yes | Yes | Prob. | 27 | BNG binding site | |
| Pro347Thr | 1039 C→A | 1 | 11 | Yes19 | - | Yes | Yes | Prob. | 38 | BNG binding site | |
| Pro347Leu | 1040 C→T | 2 | 2 | Yes55 | - | Yes | Yes | Prob. | 98 | BNG binding site | |
| Probably pathogenic | Leu46Arg | 137 T→G | 1 | 4 | No | - | Yes | Yes | Possib. | 102 | Transmembrane site |
| Ser270Arg | 810 C→A | 1 | Prbn. | No | - | Yes | Yes | Possib. | 110 | Transmembrane site | |
| ter349Gln | 1045 T→C | 1 | 2 | No | ap | NA | Yes | NA | NA | 58 Amino acids added | |
| Benign | Thr70Met | 209 C→T | 1 | No | No | - | Yes | - | Benign | 81 | |
| ROM1-rod outer membrane protein | |||||||||||
| Pathogenic | Digenic Leu114fs/ter131 | 339insG | 1 | 3 | No | NA | NA | NA | NA | NA | Digenic with RDS Leu185Pro |
| Probably pathogenic | None | ||||||||||
| Benign | Arg229His | 686 G→A | 1 | Prbn. | Yes64 | - | No | - | Benign | 29 | Rare population variant |
| Tyr234Tyr | 702 C→T | 1 | Prbn. | No | NA | NA | NA | NA | NA | Silent substitution | |
| Met271Thr | 812 T→C | 1 | Prbn. | Yes64 | - | No | - | Benign | 81 | Rare population variant | |
| Arg287Trp | 859 C→T | 1 | No | No | - | Yes | - | Prob. | 101 | ||
| RP1-RP1 protein | |||||||||||
| Pathogenic | Leu762fs/ter777 | 2285_2289del | 3 | 4 | Yes26 | fs | NA | NA | NA | NA | |
| Arg677ter | 2029 C→T | 3 | 20+ | Yes32 | ps | NA | NA | NA | NA | ||
| Gly723ter | 2167 G→T | 1 | 2 | Yes‡ | ps | NA | NA | NA | NA | ||
| Probably pathogenic | None | ||||||||||
| Benign | His1034Arg | 3101 A→G | 1 | No | No | - | NA§ | - | NA§ | 29 | .99/.01 in CEPH |
| Leu1808Pro | 5423 T→C | 1 | Prbn. | Yes32 | - | NA§ | - | NA§ | 98 | Family has another pathogenic mutation | |
| RP9 (PAP1)-Pim-1 associated protein | |||||||||||
| Pathogenic | None | ||||||||||
| Probably pathogenic | None | ||||||||||
| Benign | Lys210Arg | 629 A→G | NA | No | No | - | NA§ | NA§ | NA§ | NA§ | .73/.23 in white control subjects |
| RPGR-X-linked retinitis pigmentosa GTPase regulator | |||||||||||
| Pathogenic | Arg195fs/ter229 | ORF15+558del | 1 | 6 | Yes65 | fs | NA | - | NA | NA | |
| Glu256fs/ter492 | ORF15+764_765del | 1 | 11 | No | fs | NA | - | NA | NA | ||
| Probably pathogenic | None | ||||||||||
| Benign | None | ||||||||||
Families, number of families in the cohort with this mutation; Scores, evidence used to evaluate pathogenicity: (1) Seg., segregating in family; No, discordant segregation in family and/or present in control subjects; Prbn., observed in proband only; numbers represent affected with variant if more than proband; (2) Prior, prior publications with independently ascertained families, if known. (3) Struct.: predicted consequences to protein structure; as, abnormal splicing; ap, abnormal protein; fs, frame shift; ps, premature stop; -, no evidence. (4) SIFT, sorting intolerant from tolerant (http://blocks.fhcrc.org/sift/SIFT.html)42 as a measure of sequence conservation; No, not conserved or conserved in a few species only; Yes, conserved in several or all species tested; NA, not applicable; (5) Funct., amino acid change in a biologically relevant functional site; -, no evidence; NA, not applicable; (6) PolyP., PolyPhen (polymorphism phenotyping, http://www.bork.emblheidelberg.de/-PolyPhen)41 ratings for amino acid substitutions; Prob., probably pathogenic; Possib., possibly pathogenic; Benign, no evidence of pathogenicity; NA, not applicable; (7) Gran., Grantham score43 for chemical change of amino acid substitutions; NA, not applicable. To measure the severity of amino acid substitutions we used the chemical difference matrix of Grantham, which estimates the distance between amino acids based on side-chain composition, polarity, and molecular volume. Benign amino acid substitutions tend to have distance scores <70, whereas disease-causing substitutions are more likely to have scores >70.66 For disease-causing substitutions in rhodopsin, Grantham distances average >91.67
Kajiwara K, et al. IOVS 1992; 33:ARVO Abstract 1396.
Stone EM, et al. IOVS 1993; 34:ARVO Abstract:1149.
Grimsby JL, et al. IOVS 2000; 41:ARVO Abstract:192.
NA, no structures available for PolyPhen and/or SIFT comparative analysis (RP1) or sequence too repetitive for analysis (PAP1).