rs387906623

Positions:

• chr15-48460258-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.5284G>A​(p.Gly1762Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1762C) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.68

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 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 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 chr15-48460258-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1723869.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.
• PP5: Variant 15-48460258-C-T is Pathogenic according to our data. Variant chr15-48460258-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 29697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48460258-C-T is described in Lovd as [Likely_pathogenic]. Variant chr15-48460258-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.5284G>A	p.Gly1762Ser	missense_variant	43/66	ENST00000316623.10
FBN1	NM_001406716.1	c.5284G>A	p.Gly1762Ser	missense_variant	42/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.5284G>A	p.Gly1762Ser	missense_variant	43/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152074 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74392

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Geleophysic dysplasia 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Pars Genome Lab	Sep 08, 2021	we found this variant in a 6-year-old girl with bone dysplasia. -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics, Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 04, 2018	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2022	Not observed in large population cohorts (gnomAD); 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: 25525159, 25979247, 24339047, 21683322, 29191498, 27935852, 29620724, 31350823, 32005694, 33030311, 34006472, 33082559) -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.5284G>A (p.G1762S) alteration is located in exon 43 (coding exon 42) of the FBN1 gene. This alteration results from a G to A substitution at nucleotide position 5284, causing the glycine (G) at amino acid position 1762 to be replaced by a serine (S)._x000D_ _x000D_ Based on the available evidence, the FBN1 c.5284G>A (p.G1762S) alteration is classified as pathogenic for FBN1-related acromelic dysplasias; however, it is unlikely to be causative of either Marfan syndrome and related fibrillinopathies or Marfan lipodystrophy syndrome. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.5284G>A alteration has been previously reported as a recurrent de novo in multiple unrelated individuals with geleophysic dysplasia and acromelic dysplasia (Fan, 2021; Le Goff, 2011; Sun, 2020). Additionally, this alteration has been observed in heterozygous state in multiple other related and unrelated individuals with geleophysic and acromelic dysplasia (Cheng, 2018; Klein, 2014; Le Goff, 2011; Maddirevula, 2018; Marzin, 2021; Piccolo, 2019; Verberne, 2022). This amino acid position is highly conserved in available vertebrate species. Functional analysis by Jensen et al. (2015) demonstrated that the p.G1762S alteration resulted in normal or near normal protein secretion, consistent with other alterations associated with geleophysic dysplasia. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

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 10, 2023

ClinVar contains an entry for this variant (Variation ID: 29697). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN1 protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with geleophysic dysplasia (PMID: 21683322, 27935852, 29620724). In at least one individual the variant was observed to be de novo. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1762 of the FBN1 protein (p.Gly1762Ser). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.064	T
Vest4		0.63
MutPred		0.56		Loss of catalytic residue at G1762 (P = 0.0635);
MVP		0.86
MPC		0.55
ClinPred		0.99	D
GERP RS		5.2

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: rs387906623; hg19: chr15-48752455;