chr15-48452664-C-T

Variant names:

• chr15-48452664-C-T
• rs745680336
• NM_000138.5:c.5443G>A

Variant summary

Our verdict is Uncertain significance. The variant received -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 NM_000138.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:5 B:1
• Conservation: PhyloP100: 4.71
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.5443G>A	p.Gly1815Ser	missense	Exon 45 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.5443G>A	p.Gly1815Ser	missense	Exon 44 of 65	NP_001393645.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.5443G>A	p.Gly1815Ser	missense	Exon 45 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.5443G>A		non_coding_transcript_exon	Exon 45 of 67	ENSP00000453958.2
	FBN1	ENST00000537463.6	TSL:5	n.*1206G>A		non_coding_transcript_exon	Exon 20 of 31	ENSP00000440294.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251202 AF XY: 0.0000295

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111962

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00000420 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

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

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Uncertain:2

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Dec 01, 2022

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

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

Familial thoracic aortic aneurysm and aortic dissection Uncertain:2

Jun 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Jan 21, 2025

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function. 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) and in an individual affected with sudden unexplained death (PMID: 27930701). This variant has also been reported 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

Feb 06, 2013

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 02, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.40	D
PhyloP100		4.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.60
Sift	Benign	0.44	T
Sift4G	Benign	0.32	T
Vest4		0.58
MutPred		0.66		Loss of catalytic residue at G1815 (P = 0.0062)
MVP		0.68
MPC		1.4
ClinPred		0.87	D
GERP RS		5.5
Mutation Taster		=17/83	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs745680336; hg19: chr15-48744861;