rs76702162

chr15-48437009-G-A

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.6448C>T(p.Arg2150Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,218 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2150H) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 8.02

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 12 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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 chr15-48437008-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1753578.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 15-48437009-G-A is Pathogenic according to our data. Variant chr15-48437009-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200084.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=1}. Variant chr15-48437009-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.6448C>T	p.Arg2150Cys	missense_variant	53/66	ENST00000316623.10
FBN1	NM_001406716.1	c.6448C>T	p.Arg2150Cys	missense_variant	52/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.6448C>T	p.Arg2150Cys	missense_variant	53/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251026 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74426

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2023	The p.R2150C variant (also known as c.6448C>T), located in coding exon 52 of the FBN1 gene in the cb EGF-like #32 domain, results from a C to T substitution at nucleotide position 6448. The arginine at codon 2150 is replaced by cysteine, an amino acid with highly dissimilar properties. 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). This alteration has been observed in individuals with clinical features of Marfan syndrome (Turner CL et al. Am J Med Genet A, 2009 Feb;149A:161-70, Mannucci L et al. Clin Chim Acta, 2020 Feb;501:154-164). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 21, 2016	Variant summary: The FBN1 c.6448C>T (p.Arg2150Cys) causes a missense change involving a conserved nucleotide located in a EGF-like domain, which 4/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant alters an Arginine to Cysteine. Cysteines are vital for proper FBN1 function and alterations, although this variant creates another Cysteine instead of eliminating a Cysteine, it could lead to disruption of disulfide binding, secondary or tertiary structure, or possibly impairing fibrillin interactions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121088 (1/60544), which does not exceed the estimated maximal expected allele frequency for a pathogenic FBN1 variant of 1/8888. The variant of interest has been reported in one affected individual via a publication that does not fulfill the Ghent criteria. In addition, the variant of interest has been cited by multiple clinical diagnostic laboratories/databases with a classification of "uncertain significance." Therefore, due to the nature of this variant, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 18, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Identified independently and in conjunction with additional cardiogenetic variants in individuals referred for TAAD, Marfan syndrome, and related disorders at GeneDx, but segregation data is limited or absent at this time; Introduces a new cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1- related disorders (Collod-Beroud et al., 2003); 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: 26332594, 19161152, 33059708, 31730815, 12938084) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2150 of the FBN1 protein (p.Arg2150Cys). This variant is present in population databases (rs76702162, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Marfan syndrome (PMID: 19161152, 31730815; Invitae). ClinVar contains an entry for this variant (Variation ID: 200084). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg2150 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 28973303, 31098894; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.64	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.1	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Vest4		0.89
MVP		0.98
MPC		1.7
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: rs76702162; hg19: chr15-48729206; COSMIC: COSV57312375; COSMIC: COSV57312375;