rs794728338

chr15-48415710-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_000138.5(FBN1):c.7877T>A(p.Leu2626Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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. L2626V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000138.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 15-48415710-A-T is Pathogenic according to our data. Variant chr15-48415710-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 200200.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.7877T>A	p.Leu2626Gln	missense_variant	64/66	ENST00000316623.10
FBN1	NM_001406716.1	c.7877T>A	p.Leu2626Gln	missense_variant	63/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.7877T>A	p.Leu2626Gln	missense_variant	64/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 30, 2023

This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 2626 of the FBN1 protein (p.Leu2626Gln). 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. 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: 200200). This missense change has been observed in individuals with Marfan syndrome (Invitae). This variant is not present in population databases (gnomAD no frequency). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 01, 2018

A variant of uncertain significance was identified in the FBN1 gene. It has not been published as a pathogenic variant,nor has it been reported as a benign variant to our knowledge. The L2626Q variant was not observed inapproximately 6,500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The L2626Q variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and insilico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants innearby residues (N2624S, N2624T, N2624K, G2627R, Y2629C) have been reported in the Human Gene MutationDatabase in association with Marfan syndrome (Stenson et al., 2014). Nevertheless, the L2626Q variant does notaffect a Cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in thecalcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfansyndrome (Collod-Beroud et al., 2003). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.81
Sift	Benign	0.096	T
Sift4G	Benign	0.13	T
Vest4		0.88
MutPred		0.75		Gain of disorder (P = 0.0218);
MVP		0.89
MPC		1.4
ClinPred		0.98	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: rs794728338; hg19: chr15-48707907;