rs794728262

chr15-48427768-G-Achr15-48427768-G-C

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.7003C>T(p.Arg2335Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2335G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:5 U:2
• Conservation: PhyloP100: 3.69

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 11 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 chr15-48427768-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 495643.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 15-48427768-G-A is Pathogenic according to our data. Variant chr15-48427768-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200100.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.7003C>T	p.Arg2335Trp	missense_variant	58/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7003C>T	p.Arg2335Trp	missense_variant	57/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7003C>T	p.Arg2335Trp	missense_variant	58/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461416 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:3 Uncertain:1

Likely pathogenic, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Dec 01, 2022	NM_00138 c.7003C>T is a missense variant in FBN1 predicted to cause a substitution of an Arginine by Tryptophan at amino acid 2335 (p.Arg2335Trp). This variant was found in a proband with isolated thoracic aortic aneurysm and dissection and segregates with disease in at least 5 affected family members (PP1_strong). It has been reported 2 times in the literature in individuals with ectopia lentis but who did not meet revised Ghent criteria for Marfan syndrome (PMID: 29357934; PMID: 12203992) (PS4_moderate). This variant is not present in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis suggest that this variant may impact the protein structure (REVEL: 0.841) (PP3). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as likely pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PP1_strong, PS4_moderate, PM2_supporting, PP2, PP3. -
Likely pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	This missense variant replaces arginine with tryptophan at codon 2335 in the TGFbeta-like domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous state in at least two unrelated individuals affected with Marfan syndrome (PMID: 20135580, 35008861, 36449672), and in heterozygous state in two unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 36517271, ClinVar SCV003762201.2) and in two individuals suspected of having Marfan syndrome (PMID: 12203992, 29357934). It has been reported that this variant segregates with disease in one of the families (ClinVar SCV003762201.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 17, 2023

This missense variant replaces arginine with tryptophan at codon 2335 in the TGFbeta-like domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in homozygous state in at least two unrelated individuals affected with Marfan syndrome (PMID: 20135580, 35008861, 36449672), and in heterozygous state in two unrelated individuals affected with thoracic aortic aneurysm and aortic dissection (PMID: 36517271, ClinVar SCV003762201.2) and in two individuals suspected of having Marfan syndrome (PMID: 12203992, 29357934). It has been reported that this variant segregates with disease in one of the families (ClinVar SCV003762201.2). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 12, 2023

For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 200100). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 12203992, 29357934; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2335 of the FBN1 protein (p.Arg2335Trp). -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 04, 2018

Variant summary: FBN1 c.7003C>T (p.Arg2335Trp) results in a non-conservative amino acid change 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 245130 control chromosomes. c.7003C>T has been reported in the literature in individuals affected with Marfan Syndrome. In one family, the variant was identified in a homozygous patient of unaffected consanguineous parents, both of whom were heterozygous. The younger brother of the proband also developed symptoms of MFS, though his genotype was not reported (Voermans_2009). These data indicate that the variant may be a mild mutation 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.98
MutPred		0.79		Loss of disorder (P = 0.0031);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4

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: rs794728262; hg19: chr15-48719965; COSMIC: COSV104413903; COSMIC: COSV104413903;