Table 1.
List of CNGB1 variants associated with inherited retinal dystrophies
| Genomic start position (hg19) | Exon/intron | cDNA (NM_001297.5) | Protein change (NP_001288.3) | ACMG classification (criteria) | Phenotype | References | Frequency | ||
|---|---|---|---|---|---|---|---|---|---|
| Index Cases | Allele count | Hom Cases | |||||||
| 58001027 | IVS2 | c.159+5G>A | p.? | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57998386 | IVS3 | c.217+5G>C | p.? | Uncertain significance (PM2, PP3) | RCD | Oishi et al. (2014); This study | 3 | 4 | 1 |
| 57998062 | 4 | c.262C>T | p.(Gln88*) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Ellingford et al. (2016); Afshar et al. (2019); Carss et al. (2017) | 4 | 4 | 0 |
| 57996944 | 5 | c.315G>A | p.(Trp105*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 1 | 2 | 1 |
| 57996913 | 5 | c.346C>T | p.(Gln116*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Afshar et al. (2019); This study | 2 | 2 | 0 |
| 57996773 | 6 | c.385del | p.(Leu129Trpfs*148) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Xiang et al. (2018) | 1 | 2 | 1 |
| 57996515 | IVS6 | c.413‐1G>A | p.[=;Cys139Alafs*138]a |
Pathogenic (PVS1,PM2, PS3, PP3, PP5) |
RCD | Azam et al. (2011); Afshar et al. (2019); Charbel Issa et al. (2018) | 6 | 11 | 5 |
| 57994756 | 8 | c.522dup | p.(Lys175Glnfs*4) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Lingao et al. (2016) | 3 | 3 | 0 |
| 57994743 | IVS8 | c.534+1G>A | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | Afshar et al. (2019) | 1 | 1 | 0 |
| 57993889 | 10 | c.664C>T | p.(Gln222*) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Afshar et al. (2019); Carss et al. (2017) | 2 | 2 | 0 |
| 57993790 | IVS10 | c.761+2T>A | p.? |
Pathogenic (PVS1, PM2,PP3) |
RCD | Hull et al. (2017) | 1 | 2 | 1 |
| 57992344 | 11 | c.807G>C | p.(Gln269His) |
Likely pathogenic (PM1, PM2, PM3, PP3) |
Isolated rod dysfunction | Afshar et al. (2019); Ba‐Abbad et al. (2019) | 2 | 2 | 0 |
| 57992319 | 11 | c.832G>T | p.(Glu278*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57984446 | IVS12 | c.875‐2A>C | p.? |
Pathogenic (PVS1, PM2,PP3) |
RCD | Maeda et al. (2018) | 1 | 2 | 1 |
| 57984428 | IVS12 | c.875‐5_891del | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | Bernardis et al. (2016) | 2 | 3 | 1 |
| 57984380 | 13 | c.939G>A | p.(Trp313*) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Fradin et al. (2016); This study | 2 | 4 | 2 |
| 57984367 | 13 | c.952C>T | p.(Gln318*) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Afshar et al. (2019); Hull et al. (2017) | 2 | 2 | 0 |
| 57974234 | IVS14 | c.1122‐9G>A | p.[=; Glu374Glufs*7]b |
Pathogenic (PS3, PM2, PM3, PP1, PP3) |
RCD | Petersen‐Jones et al. (2018) | 1 | 1 | 0 |
| 57974160 | 15 | c.1187G>A | p.(Arg396Gln) | Uncertain significance (BP4, PM2) | RCD | Comander et al. (2017) | 1 | 1 | 0 |
| 57973487 | 16 | c.1219dup | p.(Glu407Glyfs*12) |
Pathogenic (PVS1, PM2,PP3) |
RCD | Charbel Issa et al. (2018); This study | 2 | 2 | 1 |
| 57973394 | 16 | c.1312C>T | p.(Gln438*) |
Pathogenic (PVS1, PM1, PM2) |
RCD | Charbel Issa et al. (2018) | 1 | 2 | 1 |
| 57973387 | 16 | c.1319G>A | p.(Trp440*) |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57965773 | 17 | c.1382C>T | p.(Thr461Met) |
Uncertain significance (BS1, PP3) |
RCD | Ellingford et al. (2016) | 1 | 1 | 0 |
| 57957231 | 18 | c.1589C>G | p.(Pro530Arg) | Uncertain significance (PP1, PP3, BS1) | RCD | Fu et al. (2013) | 1 | 2 | 1 |
| 57957207 | 18 | c.1613G>A | p.(Trp538*) |
Pathogenic (PVS1, PM2,PP3) |
RCD | This study | 1 | 2 | 1 |
| 57954451 | IVS18 | c.1644‐3C>G | p.? | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 2 | 1 |
| 57954363 | 19 | c.1729del | p.(Glu577Serfs*6) |
Pathogenic (PVS1, PM1, PM2) |
RCD | Afshar et al. (2019) | 1 | 2 | 1 |
| 57954286 | IVS19 | c.1801+5G>A | p.? | Uncertain significance (PM2, PP3) | RCD | Comander et al. (2017) | 1 | 1 | 0 |
| 57953064 | 20 | c.1896C>A | p.(Cys632*) |
Pathogenic (PVS1, PM2, PP1) |
RCD | Nishiguchi et al. (2013); Petersen‐Jones et al. (2018) | 2 | 2 | 0 |
| 57953043 | 20 | c.1917G>A | p.(Trp639*) |
Pathogenic (PVS1, PM2, PM3) |
RCD | Banerjee et al. (2017) | 1 | 1 | 0 |
| 57953019 | 20 | c.1941C>A | p.(Ser647Arg) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57953001 | IVS20 | c.1957+2T>G | p.? |
Pathogenic (PVS1,PM2, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57951242 | 21 | c.2096A>G | p.(Asp699Gly) | Uncertain significance (PM2, PP3) | RCD | Ellingford et al. (2016) | 1 | 1 | 0 |
| 57951234 | 21 | c.2093_2104dup | p.(Cys698_Ile701dup) | Likely pathogenic (PM2, PM4, PP1, PP3) | RCD | Alshamrani et al. (2020) | 1 | 1 | 0 |
| 57951166 | IVS21 | c.2166+6T>G | p.? | Uncertain significance (PM3,PP3) | RCD | This study | 1 | 1 | 0 |
| 57950065 | 22 | c.2185C>T | p.(Arg729*) |
Pathogenic (PVS1, PM2,PP3) |
RCD | Carss et al. (2017); Hull et al. (2017) | 3 | 5 | 2 |
| 57950040 | 22 | c.2210G>A | p.(Arg737His) | Uncertain significance (PM2, PP3) | RCD | Charbel Issa et al. (2018) | 1 | 1 | 0 |
| 57949241 | IVS22 | c.2218‐2A>G | p.? |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Petersen‐Jones et al. (2018) | 1 | 1 | 0 |
| 57949199 | 23 | c.2258T>A | p.(Leu753*) |
Pathogenic (PVS1, PM1, PM2) |
Isolated rod dysfunction | Afshar et al. (2019); Ba‐Abbad et al. (2019) | 2 | 2 | 0 |
| 57949173 | 23 | c.2284C>T | p.(Arg762Cys) |
Likely pathogenic (PM2, PM3, PP1, PP3, PP5) |
RCD | Azam et al. (2011); Bocquet et al. (2013); Beryozkin et al. (2015); Consugar et al. (2015); Bernardis et al. (2016); Charbel Issa et al. (2018); Petersen‐Jones et al. (2018); This study | 12 | 21 | 9 |
| 57949172 | 23 | c.2285G>A | p.(Arg762His) | Uncertain significance (PM2, PP1, PP3) | RCD | Afshar et al. (2019); Carss et al. (2017) | 2 | 4 | 2 |
| 57949164 | 23 | c.2293C>T | p.(Arg765Cys) | Uncertain significance (PM2, PP1, PP3) | RCD | Schorderet et al. (2014); Habibi et al. (2016) | 2 | 4 | 2 |
| 57949163 | 23 | c.2294G>T | p.(Arg765Leu) | Uncertain significance (PM2, PP3) | RCD | Patel et al. (2016) | 1 | 2 | 1 |
| 57946900 | IVS23 | c.2305‐2A>G | p.? |
Pathogenic (PVS1, PM2, PP1) |
RCD | This study | 2 | 3 | 1 |
| 57912979 | 24 | c.2320G>A | p.(Glu774Lys) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57946850 | 24 | c.2353A>T | p.(Lys785*) |
Pathogenic (PVS1, PM2, PP1) |
RCD | This study | 1 | 2 | 1 |
| 57946842 | 24 | c.2361C>A | p.(Tyr787*) |
Pathogenic (PVS1,PM2, PM3,PP3) |
RCD | Xu et al. (2014); Banerjee et al. (2017) | 2 | 2 | 0 |
| 57945656 | IVS25 | c.2492+1G>A | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | Charbel Issa et al. (2018) | 2 | 3 | 1 |
| 57911751 | IVS25 | c.2492+2T>G | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57938777 | IVS25 | c.2493‐2_2495delinsGGC | p.? |
Pathogenic (PVS1, PM2, PP1,PP3) |
RCD | Maranhao et al. (2015) | 1 | 2 | 1 |
| 57938781 | IVS25 | c.2493‐2A>G | p.? |
Pathogenic (PVS1, PM2, PP1, PP3) |
RCD | Maria et al. (2015) | 1 | 1 | 0 |
| 57938771 | 26 | c.2501G>T | p.(Arg834Leu) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57938764 | 26 | c.2508C>A | p.(Tyr836*) |
Pathogenic (PVS1, PM2,PP1,PP3) |
RCD | Consugar et al. (2015); Petersen‐Jones et al. (2018) | 2 | 2 | 0 |
| 57938748 | 26 | c.2524dup | p.(Thr842Asnfs*10) |
Likely pathogenic (PVS1, PM2) |
RCD | Oishi et al. (2014) | 1 | 2 | 1 |
| 57938732 | 26 | c.2540G>A | p.(Gly847Glu) | Uncertain significance (PM2, PP3) | RCD | Afshar et al. (2019) | 1 | 1 | 0 |
| 57938730 | 26 | c.2542_2543insA | p.(Gly848Glufs*4) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Charbel Issa et al. (2018) | 1 | 2 | 1 |
| 57938728 | 26 | c.2544dup | p.(Leu849Alafs*3) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Kondo et al. (2004); Consugar et al. (2015); Ge et al. (2015; Ellingford et al. (2016); Afshar et al. (2019); Hull et al. (2017) | 8 | 10 | 2 |
| 57938727 | 26 | c.2545dup | p.(Leu849Profs*3) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Petersen‐Jones et al. (2018) | 1 | 1 | 0 |
| 57938717 | 26 | c.2555C>T | p.(Pro852Leu) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 2 | 1 |
| 57937858 | 26 | c.2575G>A | p.(Val859Ile) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57938669 | 26 | c.2603G>A | p.(Gly868Asp) | Uncertain significance (PM2, PP3) | RCD | Alshamrani et al. (2020); This study | 2 | 3 | 1 |
| 57938697 | 26 | c.2662G>A | p.(Ala888Thr) | Uncertain significance (PM2, PP3) | RCD | This study | 1 | 1 | 0 |
| 57937844 | 27 | c.2676C>A | p.(Tyr892*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Afshar et al. (2019); Carss et al. (2017) | 2 | 2 | 0 |
| 57937839 | 27 | c.2681G>A | p.(Arg894His) | Uncertain significance (PP1, PP3, BS1) | RCD | Ellingford et al. (2016) | 1 | 1 | 0 |
| 57937760 | 27 | c.2760G>A | p.(Trp920*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Beryozkin et al. (2015) | 1 | 2 | 1 |
| 57937755 | 27 | c.2762_2765del | p.(Tyr921Cysfs*15) |
Pathogenic (PVS1, PM2, PP3) |
RCD | de Castro‐Miró et al. (2016); This study | 2 | 4 | 2 |
| 57937757 | 27 | c.2763C>G | p.(Tyr921*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Charbel Issa et al. (2018) | 1 | 1 | 0 |
| 57935256 | 28‐29 | c.2777‐?_2958+?del | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | Afshar et al. (2019) | 1 | 2 | 1 |
| 57937725 | IVS27 | c.2794+1G>A | p.? |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57935519 | 28 | c.2805del | p.(Glu935Aspfs*2) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Ge et al. (2015); This study | 2 | 2 | 0 |
| 57935457 | 28 | c.2867del | p.(Ile956Thrfs*15) |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 2 | 2 | 0 |
| 57935435 | 28 | c.2888_2889del | p.(Phe963Serfs*4) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Xu et al. (2014) | 1 | 1 | 0 |
| 57935346 | IVS28 | c.2893‐7G>A | p.? | Uncertain significance (PM2, PM3, PP3) | RCD | This study | 3 | 5 | 2 |
| 57935339 | 29 | c.2893G>A | p.(Gly965Ser;?) |
Likely pathogenic (PM1, PM2, PP1, PP3) |
RCD | Ellingford et al. (2016) | 1 | 1 | 0 |
| 57935311 | 29 | c.2921T>G | p.(Met974Arg) | Uncertain significance (PM1, PM2, PP3) | RCD | Dan et al. (2020); This study | 2 | 3 | 1 |
| 57935275 | 29 | c.2957A>T | p.(Asn986Ile) |
Likely pathogenic (PM1, PM2, PP3, PP5) |
RCD | Simpson et al. (2011); Abu‐Safieh et al. (2013); Bernardis et al. (2016); Ellingford et al. (2016); Patel et al. (2016); Carss et al. (2017); Charbel Issa et al. (2018); Hull et al. (2017); Pérez‐Carro et al. (2018); Afshar et al. (2019); Fuster‐García et al. (2019); This study | 24 | 34 | 10 |
| 57935266 | 29 | c.2966T>A | p.(Val989Glu) |
Likely pathogenic (PM1, PM2, PP1, PP3) |
RCD | This study | 1 | 2 | 1 |
| 57931817 | 30 | c.2978G>T | p.(Gly993Val) |
Likely pathogenic (PM1, PM2, PP1, PP3) |
RCD | Bareil et al. (2001) | 1 | 2 | 1 |
| 57931815 | 30 | c.2980G>T | p.(Glu994*) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Afshar et al. (2019); Carss et al. (2017) | 2 | 2 | 0 |
| 57931745 | 30 | c.3044_3050del | p.(Gly1015Valfs*4) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Charbel Issa et al. (2018) | 1 | 1 | 0 |
| 57931394 | 30 | c.3131_3149del | p.(Ala1044Glyfs*13) |
Pathogenic (PVS1, PM2, PP3) |
RCD | This study | 1 | 1 | 0 |
| 57931401 | 31 | c.3139_3142dup | p.(Ala1048Glyfs*13) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Carss et al. (2017); Charbel Issa et al. (2018) | 3 | 3 | 0 |
| 57931393 | 31 | c.3150del | p.(Phe1051Leufs*12) |
Pathogenic (PVS1, PM2, PP3) |
RCD | Nishiguchi et al. (2013); Ge et al. (2015); Petersen‐Jones et al. (2018); This study | 5 | 7 | 2 |
| 57921758 | IVS32 | c.3462+1G>A | p.[=;Arg1081Argfs*68]c |
Pathogenic (PVS1, PM2, PP3) |
RCD | Kondo et al. (2004) | 1 | 2 | 1 |
| Total | 170 | 236 | 67 | ||||||
Note: ACMG criteria for this study: PVS1: null variant (nonsense, frameshift, canonical ±1 or 2 splice sites or initiation codon); PS3: well‐established in vitro and/or in vivo functional studies supportive of damaging effect on the gene or gene product; PM1: located on CNBD domain; PM2: frequency on gnomAD <0.5% and no homozygous cases (if not: BS1); PM3: variant detected in trans with a pathogenic variant; PM4: protein length changes as a result of in‐frame deletions/insertions in a nonrepeat region or stop‐loss variants; PP1: cosegregation with disease verified; PP3: at least 1 predictive algorithm suggest pathogenicity (for splice variants, score ≤−10%), if not: BP4; PP5: at least three previous publications report the variant as pathogenic; BP3: in‐frame deletions/insertions in a repetitive region without a known function; BP7: a synonymous variant for which splicing prediction algorithms predict no impact to the splice sequence nor the creation of a new splice site and the nucleotide is not highly conserved.
Abbreviations: ACMG, American College of Medical Genetics and Genomics; Hom, homozygous; RCD, rod‐cone dystrophy.
Effect validated by means of minigene assay by (Saqib et al., 2015).
Effect validated by means of in vitro assay by (Petersen‐Jones et al., 2018)
Effect validated by means of in vitro assay by (Becirovic et al., 2010).