Table 2 Clinical features and ACMG/AMP evidence reassessed with application of the new PP1/PP4 criteria for FBN1 variants that were assessed as LPVs by ClinGen FBN1-specific guideline.

From: Reassessment of FBN1 variants of uncertain significance using updated ClinGen guidance for PP1/BS4 and PP4 criteria

Location	Variant	Age at time of testing (years)	Sex	Aortic root Z-score	Aortic dissection	Ectopia lentis	Systemic score (points)	Revised Ghent criteria	Family study	Literature review	Phenotype data			ACMG/AMP criteria at initial diagnosis	Classification	ACMG/AMP criteria and ClinGen FBN1-specific guideline	Reclassification	ACMG/AMP criteria and new PP1/PP4 criteria	Points-based system	Reclassification
Location	Variant	Age at time of testing (years)	Sex	Aortic root Z-score	Aortic dissection	Ectopia lentis	Systemic score (points)	Revised Ghent criteria	Family study	Literature review	Old or revised Ghent criteria	Consistent but not highly specific phenotype^a	Highly specific phenotype^b	ACMG/AMP criteria at initial diagnosis	Classification	ACMG/AMP criteria and ClinGen FBN1-specific guideline	Reclassification	ACMG/AMP criteria and new PP1/PP4 criteria	Points-based system	Reclassification
Exon	c.1884C>G p.(Cys628Trp)	22^c	M	5.39	−	+	11	+		+			+	PM1, PM2, PP4	VUS-H	PM1_S, PS4_M, PP2, PP4, PM2_P	LPV	PM1_S, PS4_M, PP2, PP4, PM2_P	13	PV
	c.2585G>A p.(Cys862Tyr)	27^c	M							+			+	No available records of variant assessment	VUS-U	PM1, PM5, PP2, PP3, PS4_P, PM2_P	LPV	PM1, PM5, PP2, PP3, PP4, PM2_P	12	PV
	c.3379G>T p.(Gly1127Cys)	64^c	F							+			+	PM2, PM5, PP3	VUS-H	PM1, PM5, PP2, PP3, PS4_P, PM2_P	LPV	PM1, PM5, PP2, PP3, PP4, PM2_P	12	PV
	c.3892A>C p.(Asn1298His)	34^c	M	11	Ascending aortic intramural hemotoma	+	6	+	2 affected				+	PM2, PP3	VUS-M	PM1, PP1, PP2, PP3, PP4, PM2_P	LPV	PM1, PP2, PP3, PP4, PM2_P	10	PV
	c.4982G>A p.(Gly1661Glu)	36^c	F	2.61	−	+	8	+					+	PM2, PM5, PP3	VUS-H	PM1, PM5, PS4_M, PP2, PP3, PP4, PM2_P	LPV	PM1, PM5, PS4_M, PP2, PP3, PP4, PM2_P	14	PV
	c.5431G>A p.(Glu1811Lys)	30^c	F							+			+	PM2, PS4_M, PP5	VUS-H	PM1, PS4_M, PP2, PP3	LPV	PM1, PS4_M, PP2, PP3, PP4	11	PV
	c.5431G>A p.(Glu1811Lys)	28^c	M							+			+	PM2, PS4_M, PP5	VUS-H	PM1, PS4_M, PP2, PP3	LPV	PM1, PS4_M, PP2, PP3, PP4	11	PV
	c.5680G>A p.(Glu1894Lys)	54^c	M							+		+		PM2, PP3	VUS-M	PM1, PP2, PP3, PS4_P, PM2_P	LPV	PM1, PP2, PP3, PP4, PM2_P	10	PV
	c.6332G>T p.(Cys2111Phe)	35^c	M	5.69	−	+	8	+					+	PM2, PM5, PP3	VUS-H	PM1, PM5, PP2, PP3, PP4, PM2_P	LPV	PM1, PM5, PP2, PP3, PP4, PM2_P	12	PV
	c.6380A>T p.(Asp2127Val)	57^c	M	10.3	−	−	11	+	1 affected	+			+	PM2, PP3, PP5	VUS-H	PM1, PM5, PS4_M, PP2, PP3, PP4, PM2_P	LPV	PM1, PM5, PS4_M, PP2, PP3, PP4, PM2_P	14	PV
	c.6448C>T p.(Arg2150Cys)	58^c	M							+			+	PM2, PP3, PS4_P	VUS-H	PM1, PS4_M, PP2, PP3	LPV	PM1, PP2, PP3, PP4, PS4_P	10	PV
	c.6490T>C p.(Cys2164Arg)	20^c	M	5.51	−	−	8	+				+		PM1, PM2, PP5	VUS-H	PM1_S, PP2, PP3, PP4, PM2_P	LPV	PM1_S, PP2, PP3, PP4, PM2_P	12	PV
	c.6707A>G p.(Tyr2236Cys)	13^c	F	1.72	−	+	7	−	2 affected				+^d	PM2, PP3	VUS-M	PM1, PP1, PP2, PP3, PP4, PM2_P	LPV	PM1, PP2, PP3, PP4, PM2_P	10	PV
	c.8020T>A p.(Cys2674Ser)	40^c	M	25.04	−	−	8	+	3 affected			+		PM1, PM2	VUS-H	PM1_S, PP1, PP2, PP3, PP4, PM2_P	LPV	PM1_S, PP2, PP3, PP4, PM2_P	12	PV
	c.8378A>G p.(Tyr2793Cys)	28^c	M							+	+			No available records of variant assessment	VUS-U	PM1, PP2, PP3, PS4_P, PM2_P	LPV	PM1, PP2, PP3, PP4, PM2_P	10	PV
Intron	c.4460−8G>A p.(?)	51^c	M	(45mm)	−	+	NE	+		+			+	PM4, PP1, PP3, PP5	VUS-H	PS4, PP1, PP3, PP4	LPV	PS4, PP3, PP4	10	PV

LPV likely pathogenic variant, NE not evaluated, PV pathogenic variant, VUS variant of uncertain significance, VUS-H variant of uncertain significance-high subclass, VUS-M variant of uncertain significance-mid subclass, VUS-U variant of uncertain significance-unsubclassified.
^aConsistent but not highly specific phenotype definition: aortic diameter at the sinus of Valsalva above the indicated Z-score (≥2 for an individual aged ≥20 years or ≥3 for an individual aged <20 years) or aortic root dissection AND systemic score ≥7 points.
^bHighly specific phenotype definition: aortic diameter at the sinus of Valsalva above the indicated Z-score (≥2 for an individual aged ≥20 years or ≥3 for an individual aged <20 years) or aortic root dissection AND ectopia lentis.
^cThis patient had been reported in the previous study of Samsung Medical Center [9].
^dHighly specific phenotype was identified in a family member with the same variant. One family member with c.6707A>G p.(Tyr2236Cys) presented an aortic root Z-score of 2.31, ectopia lentis, and a systemic score of 7 points.

Back to article page

Table 2 Clinical features and ACMG/AMP evidence reassessed with application of the new PP1/PP4 criteria for FBN1 variants that were assessed as LPVs by ClinGen FBN1-specific guideline.

Search

Quick links