rs794728162

Variant names:

• chr15-48537707-C-T
• rs794728162
• NM_000138.5:c.640G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 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. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G214D) has been classified 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
• Publications: 11 publications found

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]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48537706-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2662788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani 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.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.640G>A	p.Gly214Ser	missense_variant	Exon 7 of 66	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.640G>A		non_coding_transcript_exon_variant	Exon 7 of 67	1		ENSP00000453958.2
FBN1	ENST00000674301.2	n.640G>A		non_coding_transcript_exon_variant	Exon 7 of 68			ENSP00000501333.2
FBN1	ENST00000537463.6	n.636+4G>A		splice_region_variant, intron_variant	Intron 7 of 30	5		ENSP00000440294.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 01, 2023

Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PS1, PP4 -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Nov 20, 2018

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

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

Jun 15, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 22, 2019

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

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
PhyloP100		7.9
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
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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

Other links and lift over

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