Table 3.

Reasons for Changing the Diagnosis.

Case Number	Gene(s)	Variant(s)	Testing Laboratory	Laboratory Case-Level Classification	Clinical Geneticist Clinical-Level Classification	Reason
Cases That Were Demoted by the Clinical Geneticist
WES002	HEXA / VPS13B	c.1073+1G>AIVS9+1G>A / c.11256_11290+10del, IVS58+10delC	B	Definitive	Unlikely	Hexosaminidase A activity was normal and clinical phenotype is not consistent with Tay Sachs / Lack of a second mutation in VSP13B and phenotype is not consistent with Cohen syndrome
WES003	PANK2	c.1561G>A, p.G521R	B	Definitive	Unlikely	Brain MRI and clinical course are not consistent with PANK2-related phenotype
WES069	UPB1 / GAMT	c.917-1G>A, IVS8-1G>A / c.327G>A, p.K109K	B	Definitive	Unlikely	Negative biochemical studies for creatine deficiency syndromes and pyrimidine metabolism defects
WES090	DPYD	c.1905+1G>A, IVS14+1G>A; c.1679T>G, p.I560S	G	Definitive	Possible	Biochemical studies were consistent but clinical phenotype did not fit with the phenotype of dihydropyrimidine dehydrogenase deficiency
WES091	DMD	Deletion of exons 45-51	G	Definitive	Possible	The neurological and cardiac phenotypes, normal muscle histopathological findings, and normal CK are not consistent with the expected clinical findings of this in-frame DMD deletion
Cases That Were Promoted by the Clinical Geneticist
WES013	SCYL1	c.1039C>T, p.Q347*	A	Possible	Definitive	Clinical phenotype of the patient matched a newly described syndrome 2 years after initial analysis
WES015	UBE3B	c.2990G>C, p.R997P	A	Possible	Definitive	Facial features and clinical phenotype of the patient matched published syndrome
WES019	GRIN2B	c.1916C>T, p.A639V	A	Possible	Definitive	Clinical phenotype of the patient matched neurological findings reported in patients with GRIN2B mutations
WES028	ATP2B3 / LAMA1	c.1445G>A, p.R482H / c.6074C>T, p.T2025M; c.1741C>T, p.R2381C	G	Possible	Definitive	In vitro functional studies showed impaired PMCA3 pump function and data supported a synergistic effect with LAMA1 mutations17
WES030	ARID1B / FGFR3	c.2281G>A, p.G761S / c.445+(2_5)delTAGG, IVS4+(2_5)delTAGG	G	Possible	Definitive	The blended phenotype in the patient matched published syndromes related to these genes
WES038	CTBP1	c.991C>T, p.R331W	G	Candidate	Definitive	The patient was one of 4 patients described with a new genetic syndrome15
WES050	CYB5R3	c.250C>T, p.R84X	G	Possible	Definitive	Follow up measurement of NADH to cytochrome b5 activity and methemoglobin level in blood were consistent with CYB5R3 deficiency
WES052	GABRB2	c.909G>T, p.K303N	G	Candidate	Definitive	Subsequent publication of new syndrome in other patients12; the patient is part of an ongoing study on a series of patients to define the phenotype
WES070	GALNS / SUFU	c.1485C>G, p.N495K; c.539T>C, p.V180A / c.794_808del15, p.N265_V269del	G	Possible	Definitive	Clinical phenotype of the patient matched the two published syndromes
WES079	TELO2	c.1100G>T, p.C367F; c.2296G>A, p.V766M	G	Candidate	Definitive	The patient was 1 of 6 patients described with a new genetic syndrome16
WES121	COQ4	c.245T>A, p.L82Q; c.473G>A, p.R158Q	G	Candidate	Definitive	The patient was 1 of 4 patients described with a new CoQ10 deficiency syndrome13
WES122	SNX27	c.510C>G, p.Y170X; c.1295G>A, p.C432Y	G	Candidate	Definitive	Brain MRI and neurological phenotype were consistent with newly described syndrome11
WES126	ATM	c.3993+1G>A, IVS26+1G>A; c.5763-1050A>G, IVS39-1050A>G	G	Possible	Definitive	Re-sequencing of ATM detected a second mutation; elevated AFP and neurological findings matched the diagnosis
WES129	PGAP1	c.1546_1549delGTCA, p.V516KfsX4; c.1077T>G, p.Y359X	G	Possible	Definitive	Clinical and neurological phenotype of the patient matched published syndrome
WES131	DNMT3A	c.2645G>A, p.R882H	G	Possible	Definitive	Clinical phenotype of the patient was consistent with a newly described syndrome18
WES148	POLR3B	c.2570+5G>A, IVS22+5G>A; c.3317T>C, p.I1106T	G	Possible	Definitive	Brain MRI and clinical phenotype of the patient matched published syndrome

G: GeneDx, B: Baylor Genetics, A: Ambry Genetics.