Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss

Table 1

Summary of the four POU4F3 variants identified in this study.

Family	Nucleotide change	Amino acid change	hom/het	Allele frequency	Pathogenicity	ACMG code	Computational evidence			Origin of variant	Cosegregation
							SIFT	PolyPhen	Mutation assessor
A	c.696G>T	p.(Glu232Asp)	het	0.0001	Likely pathogenic	PM1+PM2+PM5+PP1+PP3	Deleterious	Probably damaging	High	De novo	Yes
B	c.325C>T	p.(His109Tyr)	het	—	Uncertain significance	PP1	Tolerated	Benign	Medium	De novo	Yes
C	c.635T>C	p.(Leu212Pro)	het	—	Likely pathogenic	PM1+PM2+PP1+PP3	Deleterious	Probably damaging	High	De novo	Yes
D	c.183delG	p.(Ala62Argfs22)	het	—	Pathogenic	PVS1+PM2+PP1				De novo	Yes

Allele frequency in East Asia reported by ExAC. hom: homozygous; het: heterozygous; —: no data. Notes: PVS1: null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single, or multiexon deletion) in a gene where loss of function (LOF) is a known mechanism of disease; PM1: located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation; PM2: a variant is absent from a large general population or a control cohort; PM5: novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before; PP1: segregation of a variant in a family; PP3: multiple lines of computational evidence support a deleterious effect on the gene or gene product.