15-48494209-C-T

Variant names:

• chr15-48494209-C-T
• rs1057523406
• NM_000138.5:c.2723G>A

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.2723G>A​(p.Cys908Tyr) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C908R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.12

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48494210-A-G is described in Lovd as [Likely_pathogenic].
• 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 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 15-48494209-C-T is Pathogenic according to our data. Variant chr15-48494209-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519733.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.2723G>A	p.Cys908Tyr	missense_variant	Exon 23 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2723G>A	p.Cys908Tyr	missense_variant	Exon 22 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2723G>A	p.Cys908Tyr	missense_variant	Exon 23 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Aug 23, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C908Y pathogenic mutation (also known as c.2723G>A), located in coding exon 22 of the FBN1 gene, results from a G to A substitution at nucleotide position 2723. The cysteine at codon 908 is replaced by tyrosine, an amino acid with highly dissimilar properties, and is located in the hybrid motif #02 domain. This alteration was shown to segregate with Marfan syndrome (MFS) in several members of a family. The proband, who was reported to also have MFS, did not carry this alteration, but the clinical diagnosis was described as debatable (Judge DP et al. Am J Med Genet. 2001;99:39-47). This alteration has also been reported in individuals with ectopia lentis or thoracic aortic aneurysm and dissection (Li D et al. Genet Test. 2008;12:325-30; Wang WJ et al. J Mol Med. 2013;91:37-47). Alterations at the same amino acid position, C905G and C908R, have also been detected in patients with MFS (Haine E et al. J Bone Miner Res. 2015;30:1369-76; Katzke S et al. Hum Mutat. 2002;20:197-208; Stheneur C et al. Eur J Hum Genet. 2009;17:1121-8). The majority of FBN1 mutations identified to date have involved the substitution or generation of cysteine residues within cbEGF domains (Vollbrandt T et al. J Biol Chem. 2004;279(31):32924-32931). And internal structural analysis indicates that p.C908Y eliminates a conserved disulfide motif in TB-hybrid domain 2 of fibrillin-1, which is expected to result in a more dynamic structure in this part of the protein (Jensen SA et al. Structure. 2009;17:759-68). Based on the available evidence, C908Y is classified as a pathogenic mutation. -

Isolated thoracic aortic aneurysm Pathogenic:1

Sep 01, 2018

Department of Vascular Biology, Beijing Anzhen Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Sep 05, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FBN1 c.2723G>A (p.Cys908Tyr) results in a non-conservative amino acid change located to the second hybrid motif (Li 2008) in 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 246192 control chromosomes (gnomAD and publication data). The variant, c.2723G>A, has been reported in the literature in multiple individuals affected with Marfan Syndrome (Judge 2001, Li 2008). The variant was shown to segregate with the disease in these two families, with all the patients having somewhat atypical (i.e. mild to moderate) features. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Feb 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FBN1-related disorder Pathogenic:1

Jun 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.2723G>A variant is predicted to result in the amino acid substitution p.Cys908Tyr. This variant has been reported in multiple unrelated individuals with Marfan syndrome or related phenotypes and found to segregate within families. Of note, intrafamilial phenotypic variability has been documented for this variant (Judge et al. 2001. PubMed ID: 11170092; Li et al. 2008. PubMed ID: 18471089; Table S3, Li et al. 2021. PubMed ID: 33824467). This variant has not been reported in a large population database, indicating this variant is rare. Different nucleotide substitutions affecting the same amino acid (p.Cys908Gly, p.Cys908Arg, p.Cys908Trp, and p.Cys908Ser) have been reported in individuals with Marfan syndrome or related phenotypes (Human Gene Mutation Database). Taken together, the c.2723G>A (p.Cys908Tyr) variant is interpreted as pathogenic. -

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

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 908 of the FBN1 protein (p.Cys908Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with thoracic aortic aneurysm and dissection (PMID: 11170092, 18471089, 33824467). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 519733). 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%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.94	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Vest4		0.98
MutPred		0.89		Gain of phosphorylation at C908 (P = 0.0186);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8

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: rs1057523406; hg19: chr15-48786406;