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. 2022 Nov 12;64(1):89–104. doi: 10.1007/s13353-022-00733-9

Table 2.

Variants in LCA-associated genes identified in 27 Polish families

Family no. Mode of inheritance Gene1 Causative and coexisting variants Pathogenicity prediction in protein level Classification according to ACMG3 Allele frequency (gnomAD browser)4 Molecular method of searching the variants5
Nucleotide Exon/intron no. Protein Status SIFT PROVEAN PolyPhen-22
23 AR CEP290 c.1753C>T e.18 p.Q585* Het - - - P None WES
c.2991+1655A>G i.26 p.C998* Het - - - P None NGS panel
40 NGS panel
46
24 AR LCA5 c.1555_1558del e.8 p.F519Mfs*73 Hom - - - LP None WES
25 AR GUCY2D c.2302C>T e.12 p.R768W Het Damaging Deleterious P. damaging P 0.000151 WES
c.2598G>C e.14 p.K866N Het Damaging Deleterious P. damaging VUS 0.0000065
CEP290 c.4577A>T e.35 p.E1526V Het Damaging Neutral P. damaging VUS 0.0000241
26 AD CRX c.585C>A e.4 p.Y195* Het - - - P None WES
27 AR CRB1 c.1457T>C e.6 p.L486P Het Damaging Deleterious P. damaging LP None WES
c.2843G>A e.9 p.C948Y He Damaging Deleterious P. damaging P 0.000212
28 AR CEP290 c.289G>T e.5 p.E97* Het - - - P 0.0000226 WES
c.2991+1655A>G i.26 p.C998* Het - - - P None
29 AR RPGRIP1 c.2465_2468dup e.17 p.A824Ifs*11 Hom - - - P 0.0000040 WES
30 AR NMNAT1 c.292G>C e.3 p.V98L Hom Damaging Deleterious Benign LP None WES
GUCY2D c.2179G>A e.11 p.G727S Het Damaging Deleterious P. damaging LP 0.000363
31 AR GUCY2D c.566_571del e.2 p.A189Vfs*131 Hom - - - LP None WES
insTGGGTGGAGG
32 AR GUCY2D c.2291del e.12 p.P764Lfs*20 Hom - - - P 0.0000039 WES
33 AR NMNAT1 c.769G>A e.5 p.E257L Het Tolerated Neutral Bening LP 0.000702 WES
NC_000001.11 (9970990_978973)del Het - - - P None
34 AR CRB1 c.2042G>A e.6 p.C681Y Het Damaging Deleterious P. damaging P 0.0000039 WES
c.3474T>A e.9 p.Y1158* Het - - - LP None
35 AR CEP290 c.2991+1655A>G i.26 p.C998* Het - - - P None WES
c.6277delG e.46 p.V2093Sfs*4 Het - - - P 0.0000467
36 AR CEP290 c.1078C>T e.13 p.R360* Het - - - P 0.0000264 WES
c.2991+1655A>G i.26 p.C998* Het - - - P None
37 AR LRAT c.139C>T e.2 p.R47* Hom - - - P 0.0000119 NGS panel
38 AR CRB1 c.1660del e.6 p.V554Cfs*19 Het - - - P None NGS panel
c.2042G>A e.6 p.C681Y Het Damaging Deleterious P. damaging P 0.0000039
39 AR CRB1 c.2843G>A e.9 p.C948Y Hom Damaging Deleterious P. damaging P 0.000212 NGS panel
41 AR CRB1 c.1342C>T e.6 p.Q448* Het - - - P None NGS panel
c.2843G>A e.9 p.C948Y Het Damaging Deleterious P. damaging P 0.000212
42 AR CEP290 c.1522+2T>Ca i.15 p.? Het - - - P None WES
c.5012+1G>Ab i.37 p.? Het - - - P None
43 AR CRB1 c.2042G>A e.6 p.C681Y Het Damaging Deleterious P. damaging P 0.0000039 NGS panel
c.2843G>A e.9 p.C948Y Het Damaging Deleterious P. damaging P 0.000212
44 AR NMNAT1 c.769G>A e.5 p.E257L Het Tolerated Neutral Bening LP 0.000702 NGS panel
c.839A>T e.5 p.(*280Lext*15) Het - - - LP None
45 AR CEP290 c.2991+1655A>G i.26 p.C998* Hom - - - P None NGS panel
RPGRIP1 c.1216del e.11 p.L406Yfs*36 Het - - - LP None
47 AR RPGRIP1 c.2236G>A e.16 p.(G746R) Het Damaging Deleterious P. damaging LP 0.0000122 NGS panel
c.2367+1G>A i.16 p.? Het - - - P None
48 AR CEP290 c.2991+1655A>G i.26 p.C998* Het - - - P None NGS panel
c.5587-1G>C i.40 p.? Het - - - P 0.0000143
49 AR CEP290 c.2991+1655A>G i.26 p.C998* Het - - - P None NGS panel
c.4882C>T e.37 p.Q1628* Het - - - P 0.0000369

Novel variants are marked in bold. The hyphen means that the prediction in protein level was not performed for the variant (nor necessary or improper for this variant)

1The reference sequences of the genes, in which the variants were detected, were as follows: CEP290 NM_025114.4, CRB1 NM_201253.2, GUCY2D NM_000180.4, NMNAT1 NM_002431.4, RPGRIP1 NM_020366, CRX NM_000554.6, LRAT1 NM_004744.3, LCA5 NM_001122769.3, and IQCB1 NM_001023570.4

2PolyPhen2: P. damaging probably damaging

3Classification according to ACMG: P pathogenic, LP likely pathogenic, VUS uncertain significance

4Allele frequency is listed according to GnomAD (Genome Aggregation Database), accessed 18 February 2022

a, bSplicing variants submitted to additional potential pathogenicity prediction in protein level analyses with the use of CADD and Fathmm software. The results of the analyses revealed that both variants are deleterious. For the variant c.1522+2T>C in the CEP290 gene, the CADD score is 33 and the Fathmm score is 0.99. For the variant c.5012+1G>A in the CEP290 gene, the CADD score is 25.5 and the Fathmm score is 0.99

5WES was conducted in patients diagnosed with LCA from May 2020 to April 2021, while NGS retinal panel was applied in these patients, who were referred to the genetic clinic before May 2020 and after April 2021