. 2022 Aug 26;7(1):e001064. doi: 10.1136/bmjophth-2022-001064

Table 1.

Rare coding variants detected in probands with paediatric cataract

Family ID	Phenotype	Gene	Genomic change	Coding change	Protein change	gnomAD popmax	CADD/Polyphen2/SIFT/ PROVEAN	Seg	First publication	ACMG-AMP
Pathogenic/Likely pathogenic variants
CRCH21	Central	GJA3	Chr13:20 717 252G>A	NM_021954.4:c.176C>T	p.(Pro59Leu)	0	27.7/P^rD/D/D	Yes	Bennett et al³⁷	LP
CRCH90	Dense nuclear	GJA3	Chr13:20 717 372G>A	NM_021954.4:c.56C>T	p.(Thr19Met)	0	27.3/P^rD/D/D	Yes	Santhiya et al³⁸	LP
CRCH29	–	CRYAA	Chr21:44589243C>T	NM_000394.4:c.34C>T	p.(Arg12Cys)	0	28/P^rD/D/D	Yes	Hansen et al²⁴	LP
CRCH38	Central posterior cortical with dots	COL4A1	Chr13:110833673C>T	NM_001845.6:c.2159G>A	p.(Gly720Asp)	0	23.9/P^rD/D/D	Yes	Sibon et al³³	LP
		MIR184	Chr15:79502181T>C	NR_029705.1:n.52T>C	n/a	0	16.87/-/-/-	Yes	–	VUS
CSA168	Lamellar/zonular	HSF4	Chr16:67 199 491A>G	NM_001040667.3:c.190A>G	p.(Lys64Glu)	0	29.4/P^rD/D/D	De novo?	Berry et al²³	LP
CRCH28	Posterior subcapsular	PITX3	Chr10:103990272C>A	NM_005029.4:c.908G>T	p.(Ter303LeuextTer100)	0	18.39/-/-/-	Yes	–	LP
		EYA1	Chr8:72 127 864G>A	NM_000503.6:c.1460C>T	p.(Ser487Leu)	0.001	22.8/B/T/N	No	–	B
CSA182	Posterior sutural	BFSP1	Chr20:17 475 593del	NM_001195.5:c.1124del	p.(Glu375Glyfs Ter2)	0	32/-/-/-	Yes	–	LP
CRVEEH77	Nuclear or dense total	GJA8	Chr1:147380647C>T	NM_005267.5:c.565C>T	p.(Pro189Ser)	0	25.7/P^rD/D/D	Yes	Hansen et al²⁴ Fernández-Alcalde et al*²⁵	LP
Variants of uncertain significance with evidence towards pathogenicity
CRCH137	Lamellar	GJA8	Chr1:147 380 146G>A	NM_005267.5:c.64G>A	p.(Gly22Ser)	0	26.9/P^rD/D/D	Yes	Wang et al²⁷ Fernández-Alcalde et al²⁵ Ye et al*²⁸	VUS
CTAS71	Central nuclear	GJA8	Chr1:147380470_147380472del	NM_005267.5:c.388_390del	p.(Lys131del)	0	14.76 /-/-/N	n/a	–	VUS
CSA192	–	GJA3	Chr13:20 717 385G>T	NM_021954.4:c.43C>A	p.(Gln15Lys)	0	24.2/P^sD/D/N	n/a	–	VUS
CRVEEH79	Blue dot	LEMD2	Chr6:33756893T>C	NM_001348710.2:c.1A>G	p.(?)	0	23.2/B/D/N	Yes	–	VUS
CSA93	Dense post central with lenticonus	PRX	Chr19:40904522C>T	NM_020956.2:c.386G>A	p.(Arg129His)	0	18.86/P^sD/T/N	Yes	–	VUS
CTAS34	Anterior polar & nuclear	CRYBB1	Chr22:27 008 054A>T	NM_001887.4:c.281T>A	p.(Ile94Asn)	0	25.6/P^rD/D/D	Yes	–	VUS
		MIP	Chr12:56847410C>T	NM_012064.4:c.490G>A	p.(Val164Ile)	1.0×10^–4	15.54/B/T/N	RP?	–	VUS
CQLD130	–	BFSP2	Chr3:133119192C>T	NM_003571.4:c.265C>T	p.(Arg89Trp)	1.0×10^–4	23.2/P^rD/T/D	RP?	–	VUS
CRCH4	Nuclear	MIP	Chr12:56848060C>T	NM_012064.4:c.338G>A	p.(Arg113Gln)	0	29.1/P^rD/D/D	RP?	–	VUS
Variants of uncertain significance that are unlikely to be causing disease
CSA158	Lamellar or cortical	CYP51A1	Chr7:91761099C>T	NM_000786.4:c.280G>A	p.(Ala94Thr)	0	28.8/P^rD/D/N	Yes	–	VUS
		WFS1	Chr4:6302631C>T	NM_001145853.1:c.1109C>T	p.(Ala370Val)	0	25.9/P^rD/T/N	No	–	VUS
CRCH5	Mid-periphery cortical dots, anterior polar	LONP1	Chr19:5 694 473G>A	NM_001276480.1:c.1657C>T	p.(Pro553Ser)	0	26.1/P^rD/D/D	No †1/1	–	VUS
CSA178	Lamellar	IARS2	Chr1:220 279 332G>C	NM_018060.4:c.1166G>C	p.(Gly389Ala)	0	26.8/P^rD/D/D	No	–	VUS
CQLD88	–	FBN1	Chr15:48 779 550G>A	NM_000138.5:c.3422C>T	p.(Pro1141Leu)	6.4×10^–5	28/P^rD/D/D	RP?	–	VUS
CSA100	Nuclear	LSS	Chr21:47 647 553G>C	NM_001001438.3:c.232C>G	p.(Leu78Val)	6.5×10^–5	16.77/B/T/N	No	–	VUS

Rare coding variants identified in the probands and assessment of cosegregation in the family. Section 1; pathogenic variants, section 2; variants of uncertain significance and section 3; variants unlikely to be disease-causing. Genomic change reported using human reference genome hg19. ‘–’ indicates data not available, n/a indicates not applicable. gnomAD popmax minor allele frequency represents highest frequency observed in V.2.1.1 data release. Variant predicted functional effects using CADD version 1.6^{39 40} with PHRED score given; Polyphen-2⁴¹ ‘P^rD’ probably damaging, ‘P^sD’ possibly damaging, ‘B’ benign, SIFT⁴² ‘D’ damaging, ‘T’ tolerated, PROVEAN⁴³ ‘D’ damaging, ‘N’ neutral, ‘–’ scoring unavailable. Seg; cosegregation in the family either Yes, No, de novo?, RP? if possible reduced penetrance, or ‘n/a’ singleton and not applicable. Variant interpretation based on the ACMG-AMP guidelines.¹⁵

*Reported alternate amino acid change at same location.

†1/1 homozygous observation of variant in proband.

ACMG, American College of Medical Genetics and Genomics; B, benign; LP, likely pathogenic; n/a, not available; P, pathogenic; VUS, variant of uncertain significance.