rs794728185

Positions:

• chr15-48499005-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The ENST00000316623.10(FBN1):​c.2147G>A​(p.Gly716Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G716R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 ENST00000316623.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 6.29

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 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000316623.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48499006-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3068020.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.852
• PP5: Variant 15-48499005-C-T is Pathogenic according to our data. Variant chr15-48499005-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199989.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2147G>A	p.Gly716Glu	missense_variant	18/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2147G>A	p.Gly716Glu	missense_variant	17/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2147G>A	p.Gly716Glu	missense_variant	18/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Marfan syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 23, 2023	The c.2147G>A variant in FBN1 has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 199989] as Likely Pathogenic with respect to Marfan syndrome. The c.2147G>A variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.2147G>A variant in FBN1 is located in exon 18 of this 66-exon gene and predicted to replace an evolutionarily conserved glycine amino acid with glutamic acid at position 716 of the encoded protein. In silico predictions are in favor of damaging effectfor p.(Gly716Glu) variant's effect [(CADD v1.6 = 24.1, REVEL = 0.645)]; however, there are no functional studies to support or refute these predictions. Variants nearby p.(Gly716) residue within the kinase domain have been reported in the literature [PMID: 18435798] in individuals with Marfan syndrome. Based on available evidence this c.2147G>A p.(Gly716Glu) variant identified in FBN1 is classified as Likely Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2013

p.Gly716Glu (GGA>GAA): c.2147 G>A in exon 18 of the FBN1 gene (NM_000138.4) The Gly716Glu variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly716Glu results in a non-conservative amino acid substitution of non-polar Glycine with a negatively charged Glutamic acid at a position that is conserved across species. In silico analysis predicts Gly716Glu is damaging to the protein structure/function. Mutations in nearby residues (Cys711Tyr, Gly721Cys, Asp723Val, Asp723Ala, Ile724Val, Ile724Arg) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly716Glu variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Gly716Glu is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.The variant is found in TAAD panel(s). -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 27, 2023

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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 716 of the FBN1 protein (p.Gly716Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 199989). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 24, 2023

Variant summary: FBN1 c.2147G>A (p.Gly716Glu) results in a non-conservative amino acid change located in the TGF-beta binding protein domain (Baudhuin_2019) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251490 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowlege, c.2147G>A has not been reported in the literature in individuals affected with Marfan Syndrome and no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 31227806). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Both submitters classified the variant as likely pathogenic, however without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0050	D
Vest4		0.64
MutPred		0.24		Loss of glycosylation at P715 (P = 0.1213);
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs794728185; hg19: chr15-48791202;