Table 3.

Information on identified candidate mutations in congenital anomalies of the kidney and urinary tract genes known to cause isolated or syndromic congenital anomalies of the kidney and urinary tract

Family Identificationa	Gene	Mode of Transmission	Nucleotide Change	Amino Acid Change	State	Evolutionary Conservationb	PP2 SIFT MT	CADD Score	EVSc	gnomADc	ACMGd	HGMDe	Phenotypes	Segregation
A387	KAT6Bf	Dominant	c.2152C>T	p.Arg 718Trp	Het	Saccharomyces cerevisiaeg	0.983 Del. D.C.	16	/	/	Uncertain significance	Gene	L RA, R hydronephrosis; progressive renal impairment	Variant inherited from father (affection status unknown)
A870	NOTCH2f	Dominant	c.3556T>A	p.Tyr 1186Asn	Het	Danio rerio	0.854 Del. D.C.	18	0/1/4299	0/12/277048	Uncertain significance	Gene	BL VUR nevus pigmentosus R supranummery nipple	Variant inherited from mother (affection status unknown)
A3401	NOTCH2f	Dominant	c.6767G>A	p.Arg 2256His	Het	Ciona intestinalish	0.862 Del. D.C.	15	0/1/4299	0/12/246058	Uncertain significance	Gene	R RHD, L UVJO	Variant inherited from father (affection status unknown); segregates in two affected siblings
													PUV
B17	KMT2Df	Dominant	c.13190G>T	p.Gly 4397Val	Het	Drosphilia melanogaster	0.960 Del. D.C.	11	/	/	Uncertain significance	Gene	L RA	NA
A3095	NSDHLf	X-linked recessive	c. 842G>A	p.Arg 281His	Hemi	X. tropicalis	0.899 Del. D.C.	12	/	0/6/8/199924	Uncertain significance	Gene	Prune belly syndrome	NA
													L RA
A5063	EP300f	Dominant	c.1781C>T	p.Thr594Met	Het	D. melanogasteri	0.999 Del. D.C.	32	/	0/17/246260	Uncertain significance	Gene	BL MCDK	Variant inherited from father (affection status unknown); segregates in two affected siblings
B258	TP63f	Dominant	c.799G>A	p.Val267Ile	Het	C. intestinalisj	0.802 Tol. D.C.	22	/	0/3/246070	Uncertain significance	Gene	L UPJO	NA
A3957	NOTCH2f	Dominant	c.6892C>T	p.Arg2298Trp	Het	D. rerio	0.609 Del. D.C.	11	/	0/1/245696	Uncertain significance	Gene	BL hydronephrosis	NA
													Anorectal malformation
A3960	FGFR1f	Dominant	c.1426C>T	p.Arg476Trp	Het	D. rerio	1.000 Del. D.C.	6	/	0/4/277084	Uncertain significance	Gene	L RA, R VUR	NA
													Hypospadias
													Bladder extrophy
B1307	AMER1f	Dominant	c.185G>T	p.Gly62Val	Het	D. rerio	0.813 Tol. D.C.	19	0/1/1/2427	0/4/9/200427	Uncertain significance	Gene	R MCDK	NA
B1398k	OFD1f	X-linked	c.936–2A>G	100% ESS	Het	—	/	NA	0/0/1/2427	0/8/23/198443	Uncertain significance	Gene	BL VUR	Variant inherited from mother (affection status unknown)
													R hydronephrosis
B1440	HOXA13f	Dominant	c.25C>T	p.Pro9Ser	Het	D. rerio	0.992 Tol. D.C.	18	/	0/28/226114	Uncertain significance	Gene	BL hydronephrosis	NA
													BL RHD, PUV
													Facial dysmorphism
A2904	FGFR3f	Dominant	c.1663G>A	p.Val555Met	Het	D. melanogaster	0.985 Del. D.C.	19	/	0/48/274072	Likely pathogenic	DM	R RHD, VUR	NA
B120	OFD1f	Dominant	c.517+1G>A	100% ESS	Het		/	NA	/	/	Pathogenic	Gene	R MCDK	NA
													L duplex
													L VUR, ureterocoele
B1652k	FLNAf	X-linked recessive	c.6348C>G	p.His2116Gln	Hemi	Caenorhabditis elegans	0.955 Del. D.C.	12	/	/	Uncertain significance	Gene	Prune belly syndrome	Variant inherited from mother (affection status unknown)
													Neurogenic bladder
													BL VUR

PP2, PolyPhen 2; SIFT, Sorting Intolerant from Tolerant; MT, Mutation Taster; CADD, Combined Annotation Dependent Depletion; EVS, Exome Variant Server; gnomAD, Genome Aggregation Database; ACMG, American College of Medical Genetics; Het, heterozygous; Del., deleterious; D.C., disease causing; /, data not available; L, left; RA, renal agenesis; R, right; BL, bilateral; VUR, vesicoureteric reflux; RHD, renal/hypodysplasia; UVJO, ureterovesical junction obstruction; PUV, posterior urethral valve; NA, not available; Hemi, hemizygous; MCDK, multicystic dysplastic kidney; Tol., tolerated; UPJO, ureteropelvic junction obstruction; —, not applicable; ESS, essential splice site; DM, disease mutation.

^aUnique family identification number.

^bEvolutionary conservation was assessed across phylogeny over eight species: Mus musculus, Gallus gallus, Xenopus tropicalis, Danio rerio, Caenorhabditis elegans, Ciona intestinalis, Drosphilia melanogaster, and Saccharomyces cerevisiae. If conservation is interrupted in one species but otherwise preserved across phylogeny, additional information is outlined.

^cVariant frequencies listed for homozygous/hemi (if applicable)/het/total alleles detected in the population.

^dACMG American College of Human Genetics Standards and Guidelines Classification as pathogenic, likely pathogenic, or uncertain significance.⁶⁶

^eHGMD Human Gene Mutation Database; (https://portal.biobaseinternational.com/hgmd). If the exact variant has previously been reported and classified as a pathogenic mutation that is disease causing, the variant is denoted as DM. If the gene but not the exact variant has been reported for the corresponding phenotype, gene is indicated.

^fMutations in syndromic genes identified in families with an isolated syndromic congenital anomaly of the kidney and urinary tract phenotype.

^gInterruption in conservation due to glutamine present in D. rerio and D. melanogaster.

^hInterruption in conservation due to leucine present in D. rerio.

ⁱInterruption in conservation due to glutamate present in C. elegans.

^jInterruption in conservation due to asparagine present in X. tropicalis.

^kFinding in more than two categories.