rs1131691804

Positions:

• chr15-48463123-G-A

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000138.5(FBN1):​c.5183C>T​(p.Ala1728Val) 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. 11/18 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. A1728T) 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:10
• Conservation: PhyloP100: 10.0

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 19 ACMG points.

• PM1: In a domain TB 7 (size 55) in uniprot entity FBN1_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) 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 chr15-48463124-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, 0.989
• PP5: Variant 15-48463123-G-A is Pathogenic according to our data. Variant chr15-48463123-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48463123-G-A is described in Lovd as [Likely_pathogenic]. Variant chr15-48463123-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5	c.5183C>T	p.Ala1728Val	missense_variant	42/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.5183C>T	p.Ala1728Val	missense_variant	41/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.5183C>T	p.Ala1728Val	missense_variant	42/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2024	Not observed at significant frequency 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: 21683322, 27245183, 34006472, 33082559, 36998968) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	FBN1: PM2, PM6, PS4:Moderate, PP1, PP2, PP3, PP4 -

Metaphyseal chondrodysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Geleophysic dysplasia 2 Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital

May 31, 2019

- -

Geleophysic dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The FBN1 c.5183C>T (p.Ala1728Val) missense variant has been reported in two studies and found in a total of four individuals from three unrelated families affected with FBN1-related disorders, including acromicric dysplasia and geleophysic dysplasia, all in a heterozygous state (Le Goff et al. 2011; de Bruin et al. 2016). The individual reported in Le Goff et al. (2011) study was de novo for the variant, while one patient reported in de Bruin et al. (2016) study inherited the variant from affected mother. The variant was absent from the 1000 Genomes Project, Exome Sequencing Project, the Exome Aggregation Consortium and the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.Ala1728Val is classified as likely pathogenic for FBN1-related disorders. This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. -

Acromicric dysplasia Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital

Feb 01, 2024

- -

Wide mouth;C0349588:Short stature;C1849075:Relative macrocephaly;C1849367:Wide nasal bridge Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

FBN1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The FBN1 c.5183C>T variant is predicted to result in the amino acid substitution p.Ala1728Val. This variant has been reported in multiple individuals with geleophysic dysplasia (Table 2, de novo, Le Goff et al. 2011. PubMed ID: 21683322; Table S2, Fan et al. 2021. PubMed ID: 34006472). This variant has also been reported in multiple individuals with acromicric dysplasia (Figure 1, de Bruin et al. 2016. PubMed ID: 27245183; Table S3, Marzin et al. 2020. PubMed ID: 33082559; Figure 1, Shen et al. 2023. PubMed ID: 36998968). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely 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

Oct 08, 2023

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1728 of the FBN1 protein (p.Ala1728Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of acromicric dysplasia or geleophysic dysplasia (PMID: 21683322, 27245183). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 430150). 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. This variant disrupts the p.Ala1728 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21683322). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Connective tissue disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Vest4		0.97
MutPred		0.93		Gain of methylation at K1731 (P = 0.0988);
MVP		0.98
MPC		1.4
ClinPred		0.99	D
GERP RS		6.0

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: rs1131691804; hg19: chr15-48755320; COSMIC: COSV100356139;