rs137854468

Positions:

• chr15-48487396-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5

The NM_000138.5(FBN1):​c.3379G>A​(p.Gly1127Ser) 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. 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. G1127D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 7.38

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a disulfide_bond (size 12) in uniprot entity FBN1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) 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 chr15-48487395-C-T is described in Lovd as [Likely_pathogenic].
• 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, 0.975
• PP5: Variant 15-48487396-C-T is Pathogenic according to our data. Variant chr15-48487396-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16443.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr15-48487396-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.3379G>A	p.Gly1127Ser	missense_variant	28/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3379G>A	p.Gly1127Ser	missense_variant	27/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3379G>A	p.Gly1127Ser	missense_variant	28/66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	Identified in patients with Marfan syndrome or with isolated aortic disease in published literature (PMID: 7762551, 19802897); Not observed at significant frequency in large population cohorts (gnomAD); Does not affect a cysteine or calcium-binding residue within an EGF-like domain or a TGF-binding protein domain of the FBN1 gene; cysteine substitutions in the EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (PMID: 12938084); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20082464, 12203987, 10633129, 11278305, 12511552, 19802897, 9525872, 7762551) -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 27, 2016	Variant summary: The c.3379G>A variant affects a conserved nucleotide, resulting in amino acid change from Gly to Ser. This variant is not found in 121560 control chromosomes. Francke U. et al (1995) described the association of this variant with ascending aortic disease based on the presence of this variant in multiple affected individuals from one family presented with various cardiac defects. None of these patients presented with classical MFS. Phenotypes varied from aneurysm, dissection of the ascending aorta to mild aortic root dilation. Nine affected individuals were heterozygous for the variant however one affected family member did not carry the variant of interest. While the combined clinical data on this family suggest the presence of a systemic connective-tissue disorder that overlaps with MFS, other genes associated with TAAD, such as ACTA2, TGFBR1, TGFBR2 and MYH11 have not been screened for mutations. This variant has been identified in at least 2 family members with isolated major cardiac features referred for genetic testing. None of these individuals presented with major/minor skeletal features suggestive of MFS (internal LCA data). Functional studies performed on fibroblasts from c.3379G>A carrier revealed decreased fibrillin deposition into the extracellular matrix. Taken together, this variant was classified as VUS-possibly pathogenic. -

Marfan syndrome, mild Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1995

- -

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

Mar 25, 2020

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. Experimental studies have shown that this missense change disrupts localized fibrillin folding, which does not significantly impact synthesis and trafficking, but reduces fibrillin deposition into the extracellular matrix, suggesting an extracellular dominant negative effect (PMID: 7762551, 952872, 12651868). This glycine residue is located in a FBN1 calcium-binding epidermal growth factor (cbEGF)-like domain in a position that is predicted to affect protein structure and function (PMID: 19802897). In addition, missense variants at this position of the cbEGF-like domain are overrepresented among individuals with Marfan syndrome (PMID: 12938084). This variant has been reported to segregate with ascending aortic dilatation, aneurysm, and dissection in a single family (PMID: 7762551). ClinVar contains an entry for this variant (Variation ID: 16443). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 1127 of the FBN1 protein (p.Gly1127Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.76	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.058	T
Vest4		0.96
MutPred		0.82		Gain of disorder (P = 0.0847);
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		5.6

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: rs137854468; hg19: chr15-48779593;