Table 2

Reportable new diagnoses identified via reverse phenotyping research diagnostic workflow

Research ID	Dx confidence	Reported sex	Recruitment category	Gene(s)	Variant zygosity	Consequence	HGVSc	HGVSp	gnomAD AF	100K MAF	SIFT	PolyPhen	CADD	PubMed	ClinVar listing	Segregation	ACMG classification	# of key features	System(s) involved
45	Conf	Ma	Cone dysfunction syndrome	ALMS1	Het	FS	NM_015120.4:c.10775del	NP_055935.4:p. Thr3592LysfsTer6	5.23E-05	4.77E-04				11941369, 11941370, 17594715	Path	Pat	Path	1M	M: Oph
45	Conf	Ma	Cone dysfunction syndrome	ALMS1	Het	SV	NC_000002.12:g.(73424245_73544334inv ;73424245_73427355dup ;73484777_73544334dup)							Abs	Abs	Mat	Lik_path	1M	M: Oph
47	Poss	Fe	Bardet-Biedl syndrome	BBS10	Hom	Mis	NM_024685.4:c.1790G>A	NP_078961.3:p.Gly597Asp	0	2.54E-05	Delet	Prob_dam		Abs	Abs	Bi-par	VUS	4M	M: Ren, oph, skel, endo/met
48	Conf	Ma	Rod dysfunction syndrome	NPHP1	Hom	Mis	NM_001128178.3:c.1027G>A	NP_000263.2:p.Gly343Arg	0.0001155	0.00034312	Delet	Prob_dam	35	10839884	Path	1 par (other unk)	Path	1M, 1m	M: Ren m: Oph
49	Poss	Fe	Cystic kidney disease	CEP290	Hom	Intr	NM_025114.4:c.6011+874G>T	–	0	3.81E-05				Abs	Abs	1 par (other unk)	VUS	1M, 1m	M: Ren m: CVS
50	Poss	Fe	Syndromic cleft lip and/or cleft palate	OFD1	Het	Mis	NM_003611.3:c.635G>C	NP_003602.1:p.Arg212Pro	0	1.27E-05	Delet	Poss_dam	21.2	Abs	Abs	De novo	VUS	3M	M: Fac/ora (n=2), skel
51	Prob	Ma	Joubert syndrome	CEP290	Het	Mis	NM_025114.4:c.104T>G	NP_079390.3:p.Val35Gly	0	1.00E-04	Delet	Prob_dam	33	Abs	Abs	Mat	VUS	4M	M: Oph, neu (n=3)
51	Prob	Ma	Joubert syndrome	CEP290	Het	SG	NM_025114.4:c.5668G>T	NP_079390.3:p.Gly1890Ter	9.49E-05	2.50E-04				18414213, 26092869, 16682970, 16682973, 17564967	Path	Pat	VUS	4M	M: Oph, neu (n=3)
53	Poss	Ma	Cystic kidney disease	ALMS1	Het	Mis	NM_015120.4:c.8735A>G	NP_055935.4:p.Gln2912Arg	0	5.00E-05	Delet	Poss_dam	19.03	Abs	Abs	Unk	VUS	2M, 2m	M: Ren, endo/met m: GI, CVS
53	Poss	Ma	Cystic kidney disease	ALMS1	Het	Mis	NM_015120.4:c.7412A>G	NP_055935.4:p.Asp2471Gly	0	5.00E-05	Delet	Prob_dam	25.9	Abs	Abs	Unk	VUS	2M, 2m	M: Ren, endo/met m: GI, CVS
54	Poss	Fe	Rod-cone dystrophy	ALMS1	Het	Mis	NM_015120.4:c.10831A>G	NP_055935.4:p.Arg3611Gly	3.22E-05	5.00E-05	Delet	Poss_dam	23.5	Abs	Abs	Unk	VUS	2M, 1m	M: Oph, ren m: Resp
54	Poss	Fe	Rod-cone dystrophy	ALMS1	Het	Mis	NM_015120.4:c.10377C>G	NP_055935.4:p.Ile3459Met	3.63E-05	5.00E-05	Delet	Poss_dam	23.1	Abs	VUS	Unk	VUS	2M, 1m	M: Oph, ren m: Resp
55	Conf	Fe	Single autosomal recessive mutation in rare disease	ALMS1	Het	FS	NM_015120.4:c.11794del	NP_055935.4:p. Glu3932LysfsTer18	3.99E-06	1.27E-05				Abs	Abs	Unk	Path	4M	M: Oph, endo/met (n=2), CVS
55	Conf	Fe	Single autosomal recessive mutation in rare disease	ALMS1	Het	FS	NM_015120.4:c.1735del	NP_055935.4:p. Arg579GlyfsTer17	1.61E-05	3.18E-05				26104972, 32581362, 17594715, 24462884	Path	Unk	Path	4M	M: Oph, endo/met (n=2), CVS
56	Prob	Ma	Intellectual disability	ALMS1	Het	FS	NM_015120.4:c.10775del	NP_055935.4:p. Thr3592LysfsTer6	5.23E-05	0.00047656				11941369	Path	Unk	Path	1M, 2m	M: Sens m: CVS, neu
56	Prob	Ma	Intellectual disability	ALMS1	Het	Mis	NM_015120.4:c.7510G>T	NP_055935.4:p.Ala2504Ser	8.93E-05	0.00019062	Delet	Prob_dam	25	Abs	VUS	Unk	VUS	1M, 2m	M: Sens m: CVS, neu
57	Poss	Ma	Congenital hearing impairment	ALMS1	Het	Mis	NM_015120.4:c.11429A>G	NP_055935.4:p.Tyr3810Cys	–	1.27E-05	Delet	Prob_dam	27.5	Abs	Abs	Mat	VUS	1M	M: Sens
57	Poss	Ma	Congenital hearing impairment	ALMS1	Het	Mis	NM_015120.4:c.9148A>G	NP_055935.4:p.Ile3050Val	0.0002007	0.00012708	Delet	Poss_dam	24.2	Abs	VUS	Pat	VUS	1M	M: Sens
58	Poss	Fe	Syndromic congenital heart disease	BBS1	Het	Mis	NM_024649.5:c.734C>T	NP_078925.3:p.Pro245Leu	7.16E-05	6.35E-06	Delet	Ben	23.4	Abs	VUS	Unk	VUS	1M, 1m	M: Neu m: CVS
58	Poss	Fe	Syndromic congenital heart disease	BBS1	Het	Mis	NM_024649.5:c.1313C>G	NP_078925.3:p.Thr438Arg	7.96E-05	4.45E-05	Delet	Prob_dam	25.3	Abs	VUS	Mat	VUS	1M, 1m	M: Neu m: CVS
62	Conf	Fe	Epilepsy plus other features	CEP290	Het	FS	NM_025114.4:c.5434_5435del	NP_079390.3:p. Glu1812LysfsTer5	1.14E-05	4.45E-05				Abs	Path	Unk	Path	2M	M: Oph, Neu
62	Conf	Fe	Epilepsy plus other features	CEP290	Het	Intr	NM_025114.4:c. 2991+1655A>G	–	0	0.00040031				20301475, 17964524, 20301500, 16909394, 17564967, 17345604	Path	Unk	Path	2M	M: Oph, Neu
63	Conf	Fe	Cystic kidney disease	CEP290	Het	SL	NM_025114.4:c.2T>A	NP_079390.3:p.Met1?	4.07E-06	2.54E-05				Abs	path/lik _path	Pat	Path	2M	M: Ren, oph
63	Conf	Fe	Cystic kidney disease	CEP290	Het	SG	NM_025114.4:c.4966G>T	NP_079390.3:p.Glu1656Ter	3.60E-05	1.59E-04				23559409, 25525159, 16909394, 20079931	path/lik _path	Mat	Path	2M	M: Ren, oph
66	Poss	Ma	Leber congenital amaurosis or early onset severe retinal dystrophy	CEP290	Hom	Mis	NM_025114.4:c.182T>C	NP_079390.3:p.Met61Thr	–	2.54E-05	Delet	Poss_dam	25.6	Abs	Abs	Bi-par	VUS	3M	M: Oph, neu (n=2)
67	Poss	Fe	Ultra-rare undescribed monogenic disorders	CEP290	Hom	Mis	NM_025114.4:c.5284C>T	NP_079390.3:p.Arg1762Cys	3.78E-05	9.53E-05	Delet	Poss_dam	29.6	25741868	VUS	Unk	VUS	2M, 1m	M: Oph, neu m: GI
70	Conf	Fe	Proteinuric renal disease	DYNC2H1	Het	Syn	NM_001377.3:c.11049G>A	NP_001368.2:p.Pro3683=	1.21E-05	0.00014996				Abs	Lik_path	Pat	Lik_path	2M	M: Ren, skel
70	Conf	Fe	Proteinuric renal disease	DYNC2H1	Het	SV	NC_000011.9:g. 103445518_10350188del							Abs	Abs	Mat	Lik_path	2M	M: Ren, skel
75	Poss	Ma	Distal myopathies	TMEM67	Het	Mis	NM_153704.6:c.2035G>C	NP_714915.3:p.Glu679Gln	0	5.00E-05	Delet	Prob_dam	26.5	Abs	Abs	Unk	VUS	1M	M: Ren
75	Poss	Ma	Distal myopathies	TMEM67	Het	Mis	NM_153704.6:c.755T>C	NP_714915.3:p.Met252Thr	8.36E-05	2.00E-04	Delet	Ben	23.7	26092869, 19508969, 21866095	Path	Unk	Path	1M	M: Ren

Abs, absent ; ACMG, American College of Medical Genetics and Genomics; AF, allele frequency; Bi-par, bi-parental; CADD, Combined Annotation Dependent Depletion; Conf, confident; Dx, diagnostic; Endo/met, endocrine/metabolic; Fac/ora, facial/oral; Fe, female; FS, frameshift; Hemi, hemizygous; Het, heterozygous; HGVSc, Human Genome Variation Society coding; HGVSp, Human Genome Variation Society protein; Hom, homozygous; Intr, intronic; 100K, 100 000 Genomes Project; Lik_path, likely pathogenic; M, major clinical feature; m, minor clinical feature; Ma, male; MAF, maximum allele frequency; Mat, maternal; Mis, missense; Neu, neurological; Oph, ophthalmic; 1 par (other unk), 1 parent, other unknown; Pat, Paternal; Path, pathogenic; Poss, possible; Prob, probable; Spl Reg, splice region; Ren, renal; Resp, respiratory; Sens, sensory; SG, stop gain; Skel, skeletal; SL, start loss; Spl A, splice acceptor; SV, structural variant; Syn, synonymous; Unk, unknown; VUS, variant of uncertain significance.