TABLE 3.

Detailed information of the hot variants of unknown significance—Group 3.

Case no.	Gene	Condition/OMIM	Mode of inheritance	NM	HGVSc.	HGVSp.	Classification criteria	Mode of inheritance	Zygosity	Genetic counseling	Pregnancy follow‐up
22	ACTB	#243310 Baraitser‐Winter syndrome 1, dystonia, juvenile‐onset	AD	NM_001101.5	c.659C>T	p.Ala220Val	PM1, PM2, PP2, PP3	De‐novo	Heterozygous	Monitor signs of fluid accumulation, fetal movements, and corpus callosum development	Continuation of pregnancy
23	EFNB1	# 300035 Craniofrontonasal dysplasia	XL	NM_004429.5	c.466C>T	p.Arg156Cys	PS4_supp, PM1, PM2, PP3	Maternally inherited to a male fetus	Hemizygous	Developmental delays but without cognitive impairments. It is recommended to continue the pregnancy	Continuation of pregnancy
			Dominant
24	CHD4	# 617159 Sifrim‐Hitz‐Weiss syndrome	AD	NM_001273.5	c.2903C>T	p.Ser968Phe	PM1, PM2, PP2, PP3	De‐novo	Heterozygous	Continuously assess cerebral sonographic results and proceed with additional evaluation if any abnormalities are detected	TOP, 28w after ventriculomegaly on neuro‐sonography
25	KDM3B	Diets‐Jongmans syndrome	AD	NM_016604.4	c.2812C>T	p.Arg938Cys	PM1, PM2, PP2, PP3	De‐novo	Heterozygous	Severe condition not amenable to detection through sonographic imaging	Termination of pregnancy
26	SCN1A	# 607208 Dravet syndrome	AD	NM_001165963.4	c.451C>T	p.Pro151Ser	PM1, PM2, PP2, PP3	De‐novo	Heterozygous	Severe condition not amenable to detection through sonographic imaging	Termination of pregnancy
27	PTPN23	# 618890 neurodevelopmental disorder and structural brain anomalies with or without seizures and spasticity	AR	NM_015466.4	c.3697C>A c.3886_3888delAAG	p.Arg1233Ser; p.Lys1296del	PS4_mod, PM2, PM4;	Maternally and paternally inherited	Compound heterozygous	Continuously assess fetal growth, and cerebral sonographic results and proceed with additional evaluation if any abnormalities are detected	Termination of pregnancy
				NM_015466.4			PM2, PM3, PP3
28	DDX6	# 618653 intellectual developmental disorder with impaired language and dysmorphic facies	AD	NM_004397.6	c.1078T>G	p.Ser360Ala	PM1, PM2, PP3	De‐novo	Heterozygous	Severe condition not amenable to detection through sonographic imaging	Continuation of pregnancy

Note: In accordance with the Clingen recommendation, we applied the PM2 criteria at a “support” level of significance rather than “moderate.”

Abbreviations: ACMG, American College of Medical Genetics and Genomics; AD, autosomal dominant; AR, autosomal recessive; IVH intraventricular hemorrhage; N/A, not available; PM, pathogenic moderate; PP, pathogenic supporting; PS, pathogenic strong; PVS, pathogenic very strong; TOP, termination of pregnancy; XL, X linked.