rs113111224

Positions:

• chr15-48537707-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.640G>A​(p.Gly214Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 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 17 ACMG points.

• PM1: In a domain TB 1 (size 52) in uniprot entity FBN1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FBN1. . Gene score misZ 5.0644 (greater than the threshold 3.09). Trascript score misZ 8.1787 (greater than threshold 3.09). GenCC has associacion of gene with MASS syndrome, Weill-Marchesani syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, Acromicric dysplasia, familial thoracic aortic aneurysm and aortic dissection, progeroid and marfanoid aspect-lipodystrophy syndrome, ectopia lentis 1, isolated, autosomal dominant, Marfan syndrome, Weill-Marchesani syndrome 2, dominant, isolated ectopia lentis, neonatal Marfan syndrome, stiff skin syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 15-48537707-C-T is Pathogenic according to our data. Variant chr15-48537707-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 199956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48537707-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.640G>A	p.Gly214Ser	missense_variant	7/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.640G>A	p.Gly214Ser	missense_variant	6/65		NP_001393645.1
FBN1	NM_001406717.1	c.640G>A	p.Gly214Ser	missense_variant	7/9		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.640G>A	p.Gly214Ser	missense_variant	7/66	1	NM_000138.5	ENSP00000325527	P1
FBN1	ENST00000559133.6	c.640G>A	p.Gly214Ser	missense_variant, NMD_transcript_variant	7/67	1		ENSP00000453958
FBN1	ENST00000674301.2	c.640G>A	p.Gly214Ser	missense_variant, NMD_transcript_variant	7/68			ENSP00000501333
FBN1	ENST00000537463.6	c.636+4G>A		splice_donor_region_variant, intron_variant, NMD_transcript_variant		5		ENSP00000440294

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Centre of Medical Genetics, University of Antwerp	Mar 01, 2021	PM2, PS1, PP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Medical Center Hamburg-Eppendorf	Nov 20, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2018	The p.G214S pathogenic mutation (also known as c.640G>A), located in coding exon 6 of the FBN1 gene, results from a G to A substitution at nucleotide position 640. The glycine at codon 214 is replaced by serine, an amino acid with similar properties. This mutation was initially described in a Chinese family with ectopia lentis and was reported to segregate with disease in affected family members (Sui RF et al. Zhonghua Yan Ke Za Zhi, 2004 Dec;40:828-31). Subsequently, this mutation has been described in multiple individuals with Marfan syndrome (MFS) from a variety of ethnic backgrounds, including one large family with segregation in 13 family members with MFS (Comeglio P et al. Hum. Mutat., 2007 Sep;28:928; Attanasio M et al. Clin. Genet., 2008 Jul;74:39-46; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8; Dong J et al. Mol. Vis., 2012 Jan;18:81-6; Franken R et al. Eur. Heart J., 2016 11;37:3285-3290). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jun 15, 2017

Variant summary: The FBN1 c.640G>A (p.Gly214Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution in the first TB domain of the protein (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent from the large control database ExAC (0/121464 control chromosomes). The variant has been found to segregate with classical Marfan syndrome within a four-generation nonconsanguineous Chinese family (Dong_Mol Vis_2012). It has also been identified in patients with Marfan syndrome or Marfan-related disorders (Stheneur_EJHG_2009; Franken_Euro Heart J_2016). In addition, one clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 22, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 214 of the FBN1 protein (p.Gly214Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with ectopia lentis, Marfan syndrome, aortopathy and thoracic aortic aneurysms and dissections (PMID: 15733436, 17657824, 22262941, 22772377, 26787436, 27611364). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199956). 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. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.96
MutPred		0.94		Gain of glycosylation at G214 (P = 0.0524);
MVP		0.97
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4

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: rs794728162; hg19: chr15-48829904; COSMIC: COSV57313386;