15-48520659-C-T

Position:

• chr15-48520659-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP4 PP2 PP3 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.1147G>A is a missense variant in FBN1 predicted to cause a substitution of a glutamic acid by lysine at amino acid 383 (p.Glu383Lys). This variant was found in a proband with a systemic score >7 and thoracic aortic aneurysm and/or dissection, which is a highly specific phenotype for Marfan syndrome (MFS) (PMID 11700157, internal lab data, PP4). This variant has been reported four times in ClinVar: once as pathogenic, once as likely pathogenic, and twice as uncertain significance (Variation ID: 200177). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). This variant has been reported in the literature in at least three individuals with clinical features of MFS and/or thoracic aortic aneurysm and dissection (PS4_Mod; PMID 19159394, Invitae ClinVar entry, internal lab data) and in an individual with left iliac aneurysm (GeneDx internal lab data). Computational prediction tools and conservation analysis are inconclusive with regards to a possible impact on this variant’s protein function and structure (REVEL: 0.702). This variant is located in the last nucleotide of exon 9. In silico prediction programs predict that this variant may disrupt RNA splicing (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Mod, PM2_Sup, PP2, PP3, PP4 LINK:https://erepo.genome.network/evrepo/ui/classification/CA011960/MONDO:0007947/022

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 U:2
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.
• PP4: 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.1147G>A	p.Glu383Lys	missense_variant, splice_region_variant	10/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.1147G>A	p.Glu383Lys	missense_variant, splice_region_variant	9/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.1147G>A	p.Glu383Lys	missense_variant, splice_region_variant	10/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.1147G>A	p.Glu383Lys	missense_variant, splice_region_variant, NMD_transcript_variant	10/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.1147G>A	p.Glu383Lys	missense_variant, splice_region_variant, NMD_transcript_variant	10/68			ENSP00000501333
FBN1	ENST00000537463.6	c.636+17052G>A		intron_variant, NMD_transcript_variant		5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2018

The p.E383K variant (also known as c.1147G>A), located in coding exon 9 of the FBN1 gene, results from a G to A substitution at nucleotide position 1147. The amino acid change results in glutamic acid to lysine at codon 383, an amino acid with similar properties, and is located in the TGFB#01 domain. However, this change occurs in the last base pair of coding exon 9, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. This alteration has also been reported in Marfan syndrome cohorts (Loeys B et al. Arch. Intern. Med., 2001 Nov;161:2447-54; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 383 of the FBN1 protein (p.Glu383Lys). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 11700157, 19159394; Invitae). ClinVar contains an entry for this variant (Variation ID: 200177). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Marfan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Center for Medical Genetics Ghent, University of Ghent

Nov 07, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2020

Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar (ClinVar Variant ID# 200177; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1gene; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); This variant is associated with the following publications: (PMID: 19370756, 11700157, 19159394) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.30	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.70
Sift	Benign	0.053	T
Sift4G	Uncertain	0.027	D
Vest4		0.85
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs794728325; hg19: chr15-48812856; COSMIC: COSV57313335;