Table 2.
Assessment of COL4A5 variants in the gnomAD database and gnomAD control subset
| Total gnomAD Database | gnomAD Control Subset | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Position hg19 and Protein consequence | Transcript | Affected Individuals’ Sex, Total Alleles | PolyPhen-2 | SIFT | MT | Conserved | Previously Reported; Alternative Pathogenic Residue (LOVD) | ClinVar | Pathogenicity (VarSome) | Pathogenicity (Alamut) | Evidence Supports Pathogenicity | Affected Individuals’ Sex, Total Alleles |
| 107783018 p.(Gly42S er) |
c.124G>A | 1M, 21,780 | 0a | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Noa | |
| 107783019 p.(Gly42Ala) |
c.125G>C | 1F, 182,802 |
0.003a | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Noa | 1F, 80,278a |
| 107783019 p. (Gly42Asp) |
c.125G>A | 1F, 182,802 |
0.739a | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Noa | |
| 107802357 p.(Gly69Arg) |
c.205G>C | 1F, 183,072 |
1.00b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1F)b | |
| 107807131 p.(Gly84Glu) |
c.251G>A | 1F, 182,367 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Strongb | Yes (1F)b | |
| 107811896 p.(Gly105Ala) |
c.314G>C | 1M, 183,404 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Moderateb | Yes (1M)b | 1M, 80,333b |
| 107812008 p.(Gly114Ala) |
c.341G>C | 1F, 183,513 |
1b | Delb | DCb | Glyb | No, but p.(Gly114Arg) reported in LOVDb | Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Moderateb | Yes (1F)b | 1F, 80,345b |
| 107812044 p.(Gly126Glu) |
c.377G>A | 1F, 21,871 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Moderateb | Yes (1F)b | 1F, 7600b |
| 107814670 p.(Gly138Ser) |
c.412G>A | 1F, 183,271 |
1b | Tola | DCb | Glyb | Yes, Fallerini et al.58; and p(Gly138Asp) in LOVDb | Pathogenic (no assertion criteria)b | Likely pathogenic, PM1, PM2, PM5, PP2, PP3, PP5b | Weak | Noa | |
| 107819195 p.(Gly201Ala) |
c.602G>C | 1M, 168,800 |
0.999b | Delb | DCb | Glyb | No, but p(Gly201Val), Hertz et al.61,b | Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Moderateb | Yes (1M)b | |
| 107823808 p.(Gly276Ser) |
c.826G>A | 1F, 183,230 |
1b | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | 1F, 80,319a |
|
| 107823912 p.(Gly279Arg) |
c.835G>C | 1M, 183,017 |
1b | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Moderateb | Noa | |
| 107823913 p.(Gly279Ala) |
c.836G>C | 1M, 183,034 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1M)b | 1M, 80,323b |
| p.(Gly283Val) | c.848G>T | 1F, 183,010 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1F)b | |
| p.(Gly286Cys) | c.856G>T | 1F, 182,986 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1F)b | 1F, 80,324b |
| 107829879 p.(Gly356Ala) |
c.1067G>C | 1F, 21,220 |
0.997b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1F)b | |
| 107829879 p.(Gly356Glu) |
c.1067G>A | 1M, 183,308 |
0.99b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1M)b | |
| p.(Gly512Glu) | c.1535G>A | 1M, 145,435 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1M)b | |
| 107840625 p.(Gly536Ser) |
c.1606G>A | 1F, 183,226 |
1b | Delb | DCb | Glyb | No, but p(Gly536Asp) p(Gly536Val), in LOVDb |
Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Strongb | Yes (1F)b | |
| 107844640 p.(Gly624Asp) |
c.1871G>A | 4M, 12F, 182,998 | 1b | Delb | DCb | Glyb | Yes, Slajpah et al.42,b | Pathogenic (2 stars)b | Likely pathogenic PM1, PP2, PP3, and PP5b | Strongb | Yes (4M,12F)b | 2M, 6F, 80,268b |
| 107842028 p.(Gly626Ser) |
c.1876G>A | 2M,5F, 204,674 |
1b | Delb | DCb | Glyb | Yes, Hertz et al.61,b | Likely benign (one star)a | Likely pathogenic, PM1, PM2, PM5, PP2, PP3, BP6b | Strongb | Nob | 1M, 4F, 87,809b |
| 107844640 p.(Gly656Ser) |
c.1966G>A | 1M, 181,478 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1M)b | |
| 107845177 p.(Gly702Ser) |
c.2104G>A | 1F, 129,179 |
1b | Delb | DCb | Glyb | No, but p(Gly702Val), in LOVD (VUS)b | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (1F)b | 1M, 55,168b |
| 107846274 p.(Gly743Ser) |
c.2227G>A | 2F, 148,007 |
1b | Delb | DCb | Glyb | No, but p.(Gly743Asp), Plant et al.62,b | Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Weak | Noa | 2F, 63,637a |
| 107849982 p.(Gly752Val) |
c.2255G>T | 2M, 183,227 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Strongb | Yes (2M)b | |
| 107850087 p.(Gly787Ala) |
c.2360G>C | 1F, 183,169 |
1b | Delb | DCb | Glyb | No, but p(Gly787Val), King et al.63,b |
Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Strongb | Yes (1F)b | |
| 107858210 p.(Gly822Glu) |
c.2465G>A | 1M, 182,957 |
1b | Delb | DCb | Glyb | No, but p(Gly822Arg), Cruz-Robles et al.64,b |
Not found | Likely pathogenic, PM1, PM2, PM5, PP2, PP3b | Strongb | Yes (1M)b | |
| 107865033 p.(Gly893Val) |
c.2678G>T | 1F, 180,196 |
1b | Delb | DCb | Glyb | Yes, Bekheirnia et al.,65 p(Gly893Arg), Mohammad et al.66,b | Pathogenic (no assertion criteria)b | Likely pathogenic, PM1, PM2, PM5, PP2, PP3, PP5b | Weak | Yes (1F)b | |
| p.(Gly953Val) | c.2858G>T | 249M, 442F, 204,819 |
1b | Delb | Pola | Glyb | Yes, Knebelmann et al.67,b | Conflicting interpretation, B, LB, VUSa | Benign, PM1, PP2, PP3, BS1, BS2a | Benigna | Noa | 125M, 230F, 87,876a |
| 107866020 p.(Gly961Val) |
c.2882G>T | 2M,3F, 182,593 |
0.001a | Delb | Pola | Glyb | No | Not found | VUS, PM1, PP2, BP4a | Weak | Noa | 1M, 1F, 80,233a |
| 107866037 p.(Gly967Arg) |
c.2899G>A | 1F, 181,344 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Moderateb | Yes (1F)b | |
| 107869494 p(Gly1054Asp) |
c.3161G>A | 1M, 183,204 |
1b | Delb | DCb | Glyb | LOVDb | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Moderateb | Yes (1M)b | |
| 107869553 p(Gly1074Arg) |
c.3220G>C | 1M, 183,246 |
0.073a | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Noa | |
| 107869553 p.(Gly1074Ser) |
c.3220G>A | 4M, 3F, 204,841 |
0.129a | Delb | DCb | Glyb | No | Not found | VUS, PM1, PP2, PP3, BS2a | Weak | Noa | 1M, 2F, 80,317a |
| p.(Gly1134Cys) | c.3400G>T | 1F, 180,336 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | 1F, 79,040b |
| p.(Gly1170Ser) | c.3508G>A | 1F, 174,685 |
1b | Delb | DCb | Glyb | Yesb, Inoue et al.68 | Pathogenic (no assertion criteria)b | Pathogenic, PS1, PM1, PM2, PM5, PP2, PP3, PP5b | Weak | Yes (1F)b | 1F, 76,459b |
| 107909824 p.(Gly1185Ser) |
c.3553G>A | 1F, 159,615 |
0.99b | Delb | DCb | Glyb | No | Not found | Pathogenic, PVS1, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | |
| 107911689 p.(Gly1249Arg) |
c.3745G>A | 1F, 174,771 |
0.99b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | |
| 107920766 p.(Gly1282Glu) |
c.3845G>A | 1M, 183,125 |
1b | Delb | DCb | Glyb | No, but p(Gly1282Val), in LOVDb | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1M)b | |
| 107920774 p.(Gly1285Ser) |
c.3853G>A | 1F, 183,121 |
0.026a | Tola | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Noa | 1F, 80,288a |
| 107920820 p.(Gly1300Ala) |
c.3899G>C | 1F, 182,971 |
0.999b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | |
| 107920829 p.(Gly1303Ala) |
c.3908G>C | 1M, 182,951 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1M)b | |
| 107923928 p.(Gly1321Val) |
c.3962G>T | 1F, 182,976 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | |
| 107923937 p.(Gly1324Glu) |
c.3971G>A | 1F, 182,990 |
1b | Delb | DCb | Glyb | No | Not found | Likely pathogenic, PM1, PM2, PP2, PP3b | Weak | Yes (1F)b | 1F, 80,251b |
| p.(Gly1333Cys) | c.3997G>T | 1M, 182,997 |
1b | Delb | DCb | Glyb | No, but p(Gly1333Ser), Plant et al.62,b | Not found | Pathogenic, PVS1, PM1, PM2, PM5, PP2, PP3b | Weak | Yes (1M)b | 1M, 80,243b |
| 107925082 p.(Gly1394Cys) |
c.4180G>T | 2F, 182,474 |
1b | Delb | DCb | Glyb | No | Not found | Pathogenic and predicted to result in termination codon, PP3b | Moderateb | Yes (2F)b | |
| 107929314 p.(Gly1424Ser) |
c.4270G>A | 1F, 182,592 |
1b | Delb | DCb | Glyb | Yes, LOVD, p(Gly1424Glu), Zhang et al.69,b | Not found | Likely pathogenic, PM2, PM3, PM5, PP2, PP3b | Weak | Yes (1F)b | |
| 107802385 | c.231 + 2T>C | 1M, 182,806 |
No | Not found | Pathogenic, PVS1, PM2, PP3b | Exon 3 skip likely, likely abolition of donor site (3 of 4 tools)b | Yes (1M)b | 1F, 80,152b |
||||
| 107821614 | c.780 + 1G>T | 1F, 183,138 |
No | Not found | Pathogenic, PVS1, PM2, PP3b | Exon 13 skip likely, likely abolition of donor site (4 of 4 tools)b | Yes (1F)b | 1M, 80,312b |
||||
| 107863487 | c.1340–1G>A | 1F, 183,216 |
No | Likely pathogenic (one star)b | Pathogenic, PVS1, PM2, PP3, PP5b | Exon21 skip likely, likely abolition of acceptor site (4 of 4 tools)b | Yes (1F)b | 1M, 80,317b |
||||
| 107863487 | c.2510–2A>G | 1F, 181,241 |
No | Pathogenic (no assertion criteria)b | Pathogenic, PVS1, PM2, PP3, PP5b | Exon 31 skip likely, likely abolition of acceptor site (3 of 4 tools)b | Yes (1F)b | 1M, 80,268b |
||||
| 107917984 | c.3808 + 1G>C | 1F, 169,376 |
No | Not found | Pathogenic, PVS1, PM2, PP3, PP5b | Exon 43 skip likely, likely abolition of donor site (3 of 4 tools)b | Yes (1F)b | |||||
| 107929360 | c.4315 + 1G>A | 2F, 200,378 |
No | Pathogenic (one star)b | Pathogenic, PVS1, PM2, PP3, PP5b | Exon 48 skip likely, likely abolition of donor site (3 of 4 tools)b | Yes (2F)b | |||||
| 107898559 p.(Gly1083Ter) |
c.3247_3248 delGG | 1F, 182,859 |
No | Not found | Pathogenic, PVS1, PM2, PP3b | Likely abolition of acceptor site (4 of 4 tools) interrupts reading frame prematurelyb | Yes (1F)b | 1F, 80,169b |
||||
| 54 variants assessed | 88 individuals potentially affected (29M, 59F) | 47 variants pathogenic | 47 variants pathogenic | 52 variants pathogenic | 45 missense variants conserved | 16 previous reports of pathogenicity | 9 decisions; 7 pathogenic |
51 variants predicted pathogenic in VarSome | 30 variants moderately or strongly pathogenic | 9 decisions; 7 pathogenic | 23 predicted pathogenic alleles (9M, 14F) in mean 73,849 alleles examined | |
Polyphen-2, SIFT (Sorting Intolerant from Tolerant), and MutationTaster are computational tools to assess pathogenicity, and scores of >0.80, Del, or DC are consistent with pathogenicity, respectively. Conservation of Gly among vertebrates was examined ). ClinVar uses the terms Pathogenic and Likely Pathogenic, Variant of Uncertain Significance, Benign, Likely Benign, Conflicting, and and a star system (one to four stars) for the quality of assertion. VarSome uses ACMG/AMP grading of pathogenic, LP, P, VUS, LB and B; and criteria of PVS (pathogenic very strong), PM (pathogenic moderate), PP (pathogenic supporting), BS (benign strong), etc. Although individual tools may be consistent with a pathogenic or benign classification, these are not individually sufficient to assert variant pathogenicity. The tools used here have been principally to exclude variants where the evidence is not totally supportive of pathogenicity. M, male; F, female; Tol, tolerated; DC, disease causing; and Del, deleterious, Pol polymorphism.
a
Evidence against pathogenicity.
b
Evidence consistent with pathogenicity.