Table 1.
Phenotypic diversity in COL1A1 a and COL1A2 b pathogenic variants discovered in patients with OI from the UT OI biobank
| No. | Pathogenic variant | Gene | Mutation type | Collagen defect | Protein alteration | Sillence OI type reported in the UT OI database studied cohort c | Sillence OI type reported in the Dalgleish OI variant database c |
|---|---|---|---|---|---|---|---|
| 1. Monophenotypes | |||||||
| 1.1 Mild monophenotypes | |||||||
| 1 | c.590G>A | COL1A1 | Missense | DN | p.Gly197Asp | I (1) | I (2) |
| 2 | c.3766G>A | COL1A1 | Missense | DN | p.Ala1256Thr | I (1) | I (1) |
| 3 | c.1354‐2A>G | COL1A1 | Splice site | LOF | ‐ | I (1) | I (1) |
| 4 | c.904‐9G>A | COL1A1 | Splice site | LOF | ‐ | I (2) | I (1) |
| 5 | c.579_delT | COL1A1 | Frameshift | LOF | p.Gly194Valfs*71 | I (1) | I (22) |
| 6 | c.459_delT | COL1A1 | Frameshift | LOF | p.Gly154Alafs*111 | I (1) | I (1) |
| 7 | c.3807G>A | COL1A1 | Nonsense | LOF | p.Trp1269* | I (1) | I (2) |
| 8 | c.3076C>T | COL1A1 | Nonsense | LOF | p.Arg1026* | I (1) | I (12) |
| 1.2 Moderate monophenotype | |||||||
| 1 | c.1630G>A | COL1A2 | Missense | DN | p.Gly544Ser | IV (1) | IV (1) |
| 1.3 Severe monophenotype | |||||||
| 1 | c.1165G>A | COL1A1 | Missense | DN | p.Gly389Ser | III (1) | III (3) |
| 2 | c.742G>A | COL1A1 | Missense | DN | p.Gly284Arg | III (1) | III (1) |
| 2. Polyphenotypes | |||||||
| 2.1 Less variable phenotypes | |||||||
| 2.1.1 Mild‐to‐moderate OI phenotypes | |||||||
| 1 | c.2560G>A‡ | COL1A1 | Missense | DN | p.Gly854Ser | I, IV (1) | I/IV (2) |
| 2 | c.3235G>A | COL1A1 | Missense | DN | p.Gly1079Ser | I (1) | I, IV (20) |
| 3 | c.653G>A | COL1A1 | Missense | DN | p.Gly218Asp | I (2) | IV (1) |
| 4 | c.959G>A | COL1A1 | Missense | DN | p.Gly320Asp | IV (1) | I (1) |
| 5 | c.1451G>A | COL1A2 | Missense | DN | p.Gly484Glu | IV (1) | I (2) |
| 6 | c.3305G>T | COL1A2 | Missense | DN | p.Gly1102Val | I (1) | IV (1) |
| 7 | c.750+2T>A‡ | COL1A1 | Splice site | LOF | ‐ | I, IV (1) | I (1) |
| 8 | c.3045+1G>A | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (1) |
| 9 | c.299‐1G>C‡ | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (3) |
| 10 | c.1614+1G>A | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (3) |
| 11 | c.858+1G>A‡ | COL1A1 | Splice site | LOF | ‐ | I, IV (2) | I (2) |
| 12 | c.804+1G>A | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (1) |
| 13 | c.1002+2T>C | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (1) |
| 14 | c.1299+1G>C | COL1A1 | Splice site | LOF | ‐ | IV (1) | I, IV (4) |
| 15 | c.2614‐1G>A | COL1A1 | Splice site | LOF | ‐ | IV (1) | I (1) |
| 16 | c.2523_delT | COL1A1 | Frameshift | LOF | p.Gly842Alafs*266 | I (1) | I, IV (4) |
| 17 | c.658C>T‡ | COL1A1 | Nonsense | LOF | p.Arg220* | I, IV (1) | I (11) |
| 18 | c.2089C>T | COL1A1 | Nonsense | LOF | p.Arg697* | IV (1) | I, IV (8) |
| 19 | c.1789G>T | COL1A1 | Nonsense | LOF | p.Glu597* | I (1) | IV (1) |
| 20 | c.1081C>T | COL1A1 | Nonsense | LOF | p.Arg361* | IV (2) | I (10) |
| 2.1.2 Severe‐to‐moderate phenotypes | |||||||
| 1 | c.2101G>T | COL1A1 | Missense | DN | p.Gly701Cys | III (1) | IV (1) |
| 2 | c.3226G>A | COL1A1 | Missense | DN | p.Gly1076Ser | IV (2) | III, IV (13) |
| 3 | c.1090G>A | COL1A2 | Missense | DN | p.Gly364Ser | III (1) | IV (1) |
| 4 | c.2288G>T | COL1A2 | Missense | DN | p.Gly763Val | III (1) | III/IV (2) |
| 5 | c.2324G>A | COL1A2 | Missense | DN | p.Gly775Glu | III (2) | III, IV (1) |
| 6 | c.3034G>A | COL1A2 | Missense | DN | p.Gly1012Ser | III (2) | III/IV (24) |
| 7 | c.865G>A | COL1A2 | Missense | DN | p.Gly289Ser | III (1) | III/IV, IV (2) |
| 8 | c.792+1G>A | COL1A2 | Splice site | LOF | ‐ | III (1) | IV (1) |
| 9 | c.2613+6T>C | COL1A1 | Splice site | LOF | ‐ | IV (1) | III (1) |
| 2.2 More variable phenotypes | |||||||
| 2.2.1 Opposite OI phenotypes | |||||||
| 1 | c.1072G>T‡ | COL1A2 | Missense | DN | p.Gly358Ser | I, III (1) | III (1) |
| 2 | c.2233G>C | COL1A2 | Missense | DN | p.Gly745Arg | III (1) | I (1) |
| 3 | c.874G>A | COL1A2 | Missense | DN | p.Gly292Ser | III (1) | I (5) |
| 2.2.2 Non‐lethal phenotypes | |||||||
| 1 | c.2362G>A | COL1A1 | Missense | DN | p.Gly788Ser | IV (2) | I, III, IV (8) |
| 2 | c.2461G>A‡ | COL1A1 | Missense | DN | p.Gly821Ser | I, IV (5) | I, III, IV (26) |
| 3 | c.757C>T | COL1A1 | Missense | DN | p.Arg253Phe | IV (1) | I, III, IV (11) |
| 4 | c.769G>A‡ | COL1A1 | Missense | DN | p.Gly257Arg | I, IV (1) | I, III, IV (37) |
| 5 | c.977G>A | COL1A1 | Missense | DN | p.Gly326Asp | I (1) | I, III, IV (3) |
| 6 | c.1057G>T‡ | COL1A1 | Missense | DN | p.Gly353Cys | I, IV (1) | III/IV (2) |
| 7 | c.1165G>T | COL1A1 | Missense | DN | p.Gly389Cys | I (2) | III/ IV (2) |
| 8 | c.2314G>A‡ | COL1A2 | Missense | DN | p.Gly772Ser | I, IV (1) | I, III, IV (18) |
| 9 | c.2503G>A | COL1A2 | Missense | DN | p.Gly835Ser | III (1) | I, III, IV (4) |
| 10 | c.982G>A‡ | COL1A2 | Missense | DN | p.Gly328Ser | IV, III (2) | I, III, IV (45) |
| 11 | c.1009G>A | COL1A2 | Missense | DN | p.Gly337Ser | III, IV (3) | I, III, IV (29) |
| 12 | c.1821+1G>A‡ | COL1A1 | Splice site | LOF | ‐ | III, IV, I (2) | I, IV (17) |
| 13 | c.1243C>T | COL1A1 | Nonsense | LOF | p.Arg415* | I (1) | I, III/IV (16) |
| 14 | c.1128_delT‡ | COL1A1 | Frameshift | LOF | p.Gly377Alafs*164 | I, IV, III (1) | I (9) |
| 2.2.3 Mild‐to‐lethal phenotypes | |||||||
| 1 | c.1102G>A | COL1A1 | Missense | DN | p.Gly368Ser | IV (1) | II/III, III (2) |
| 2 | c.1588G>A | COL1A1 | Missense | DN | p.Gly530Ser | III (1) | II, III, IV (12) |
| 3 | c.2299G>A | COL1A1 | Missense | DN | p.Gly767Ser | I, III, IV (3) | I, II, III, IV (34) |
| 4 | c.2596G>A | COL1A1 | Missense | DN | p.Gly866Ser | III (1) | II, III (10) |
| 5 | c.1378G>A | COL1A2 | Missense | DN | p.Gly460Ser | IV (1) | II/III, III, IV (16) |
OI types reported in the OI variant database were obtained from http://www.le.ac.uk/ge/collagen/.
DN, dominant negative; LOF, loss‐of‐function; OI, osteogenesis imperfecta; UT, University of Tartu.
a
COL1A1 GenBank reference sequence (gDNA NG_007400.1, cDNA NM_000088.3). b COL1A2 GenBank reference sequence (gDNA NG_007405.1, cDNA NM_000089.3). cThe number of reported families in the UT OI database and the number of reported cases in the Dalgleish variant database are represented in parentheses.
*
“Stop codon” in mutation nomenclature.
‡
Variants which caused variety of phenotypes intrafamilially are marked with a diesis (‡).