15-48452664-C-T

Position:

chr15-48452664-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP2

This summary comes from the ClinGen Evidence Repository: NM_00138 c.5443G>A is a missense variant in FBN1 predicted to cause a substitution of a Glycine by Serine at amino acid 1815 (p.Gly1815Ser). This variant has been reported 3 times in ClinVar: once as likely pathogenic and twice as a variant of uncertain significance (Variation ID: 200064). This variant has been reported in the literature in 2 probands. It was identified in the homozygous state in an individual with autism spectrum disorder, global developmental delays, arachnodactyly, and dysmorphic features (PMID:32655337); of note, homozygous variants of uncertain significance were identified in two other genes in this individual, and all 3 homozygous variants were found to segregate with disease in a similarly affected sibling. It was identified in another individual with sudden unexplained death in epilepsy, for which an autopsy did not identify any cardiac abnormalities (PMID:27930701). This variant was also identified in an internal proband with thoracic aortic dissection and a systemic score >7 however, a pathogenic nonsense variant in FBN1 was also identified in this individual (BP2) and was considered to explain the phenotype . This variant has been identified in 0.0033% of individuals of South Asian origin in gnomAD v2.1.1. (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets the criteria to be classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BP2 LINK:https://erepo.genome.network/evrepo/ui/classification/CA015829/MONDO:0007947/022

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

FBN1
ENST00000316623.10 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:1U:5B:1

Conservation

PhyloP100: 4.71

Variant links:

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]

FBN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -1 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN1	NM_000138.5 linkuse as main transcript	c.5443G>A	p.Gly1815Ser	missense_variant	45/66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1 linkuse as main transcript	c.5443G>A	p.Gly1815Ser	missense_variant	44/65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10 linkuse as main transcript	c.5443G>A	p.Gly1815Ser	missense_variant	45/66	1	NM_000138.5	ENSP00000325527	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251202

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727226

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:5Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Marfan syndrome

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	Dec 01, 2022	NM_00138 c.5443G>A is a missense variant in FBN1 predicted to cause a substitution of a Glycine by Serine at amino acid 1815 (p.Gly1815Ser). This variant has been reported 3 times in ClinVar: once as likely pathogenic and twice as a variant of uncertain significance (Variation ID: 200064). This variant has been reported in the literature in 2 probands. It was identified in the homozygous state in an individual with autism spectrum disorder, global developmental delays, arachnodactyly, and dysmorphic features (PMID: 32655337); of note, homozygous variants of uncertain significance were identified in two other genes in this individual, and all 3 homozygous variants were found to segregate with disease in a similarly affected sibling. It was identified in another individual with sudden unexplained death in epilepsy, for which an autopsy did not identify any cardiac abnormalities (PMID: 27930701). This variant was also identified in an internal proband with thoracic aortic dissection and a systemic score >7 however, a pathogenic nonsense variant in FBN1 was also identified in this individual (BP2) and was considered to explain the phenotype . This variant has been identified in 0.0033% of individuals of South Asian origin in gnomAD v2.1.1. (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein. The constraint z-score for missense variants affecting FBN1 is 5.06 however due to the presence of one benign argument PP2 cannot be used . In summary, this variant meets the criteria to be classified as uncertain significance for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual showing clinical features resembling Marfan syndrome (Cortini et al., 2020, DOI: 10.4103/ds.ds_16_19). This variant has been observed in homozygosity in two siblings affected with autism spectrum disorder, arachnodactyly and facial features consistent with Marfan syndrome but not affected with cardiovascular problems (PMID: 32655337). This variant has been identified in 4/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 02, 2022	The p.G1815S variant (also known as c.5443G>A), located in coding exon 44 of the FBN1 gene, results from a G to A substitution at nucleotide position 5443. The glycine at codon 1815 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and in an individual who had some overlapping features with Marfan syndrome (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Cortini F, et al. Dermatol Sin, 2020;38:98-101). This variant was also described as a homozygote in two siblings with autism, arachnodactyly and skeletal problems from a consanguineous mating. The parents were reported to be heterozygous for this alteration and absent of features of Marfan syndrome (Farajzadeh Valilou S et al. Mol Syndromol, 2020 Jun;11:62-72). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 28, 2023	This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual showing clinical features resembling Marfan syndrome (Cortini et al., 2020, DOI: 10.4103/ds.ds_16_19). This variant has been observed in homozygosity in two siblings affected with autism spectrum disorder, arachnodactyly and facial features consistent with Marfan syndrome but not affected with cardiovascular problems (PMID: 32655337). This variant has been identified in 4/251202 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2013

p.Gly1815Ser (GGC>AGC): c.5443 G>A in exon 45 of the FBN1 gene (NM_000138.4)The Gly1815Ser variant in the FBN1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Gly1815Ser results in a non-conservative amino acid substitution of a non-polar Glycine with a polar Serine at a position that is conserved across species. In silico analysis predicts Gly1815Ser is damaging to the protein structure/function. Mutations in nearby residues (Glu1811Lys, Cys1812Arg, Cys1812Tyr, Cys1818Gly, Cys1818Tyr) have been reported in association with Marfan syndrome, further supporting the functional importance of this region of the protein. Furthermore, the Gly1815Ser variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, while Gly1815Ser is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant.The variant is found in TAAD panel(s). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 02, 2024

Variant summary: FBN1 c.5443G>A (p.Gly1815Ser) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251202 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5443G>A has been reported in the literature in individuals affected with sudden unexplained death (Sanchez_2016) or autism spectrum disorder with skeletal abnormalities (Farajzadeh Valilou_2020). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32655337, 27930701). ClinVar contains an entry for this variant (Variation ID: 200064). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

0.40

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.60

Sift

Benign

0.44

Sift4G

Benign

0.32

Vest4

0.58

MutPred

0.66

Loss of catalytic residue at G1815 (P = 0.0062);

MVP

0.68

MPC

1.4

ClinPred

0.87

GERP RS

5.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over