15-48510128-C-T

Position:

• chr15-48510128-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5 PM1 PM2_Supporting PS1 PP2 PP3

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.1630G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by arginine at amino acid 544 (p.Gly544Arg). This variant impacts a critical glycine between Cys2 and Cys3 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant has been reported twice in ClinVar: once as pathogenic, and once as uncertain significance (Variation ID: 495558). This variant has been previously reported in at least 1 individual with clinical features of Marfan syndrome (MFS) (Invitae lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different nucleotide change resulting in the same amino acid substitution, missense variant at this position, c.1630G>C p.Gly544Arg, has previously been previously established as pathogenic, and was found to segregate with MFS with or without thoracic aortic aneurysm in eight affected individuals from one family (PS1; PMID 30087447, internal lab data). A different missense variant at this position, c.1630G>C p.Gly544Arg, has been found in an individual with a clinical diagnosis of MFS, and has been established as likely pathogenic (PM5; internal lab data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.918). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS1, PM1, PM5, PM2_Sup, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA392341228/MONDO:0007947/022

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:2 U:1
• Conservation: PhyloP100: 7.91

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.1630G>A	p.Gly544Arg	missense_variant	14/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1630G>A	p.Gly544Arg	missense_variant	13/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1630G>A	p.Gly544Arg	missense_variant	14/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

May 23, 2024

The NM_00138 c.1630G>A is a missense variant in FBN1 predicted to cause a substitution of a glycine by arginine at amino acid 544 (p.Gly544Arg). This variant impacts a critical glycine between Cys2 and Cys3 within a calcium binding EGF-like domain, important for interdomain packaging (PM1, PMID 31227806). This variant has been reported twice in ClinVar: once as pathogenic, and once as uncertain significance (Variation ID: 495558). This variant has been previously reported in at least 1 individual with clinical features of Marfan syndrome (MFS) (Invitae lab data). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different nucleotide change resulting in the same amino acid substitution, missense variant at this position, c.1630G>C p.Gly544Arg, has previously been previously established as pathogenic, and was found to segregate with MFS with or without thoracic aortic aneurysm in eight affected individuals from one family (PS1; PMID 30087447, internal lab data). A different missense variant at this position, c.1630G>C p.Gly544Arg, has been found in an individual with a clinical diagnosis of MFS, and has been established as likely pathogenic (PM5; internal lab data). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.918). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS1, PM1, PM5, PM2_Sup, PP2, PP3. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2024

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 544 of the FBN1 protein (p.Gly544Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 1929384, 30087447; Invitae). ClinVar contains an entry for this variant (Variation ID: 495558). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2016

Variant summary: The FBN1 c.1630G>A (p.Gly544Arg) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121128 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.028	D
Vest4		0.99
MutPred		0.87		Gain of disorder (P = 0.1115);
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555400063; hg19: chr15-48802325;