15-48485374-C-T

Variant names:

• chr15-48485374-C-T
• rs794728208
• NM_000138.5:c.3712G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PP4 PP2 PP3 PM2_Supporting PS4 PM1 PM5 PP1_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_00138 c.3712G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1238 (p.Asp1238Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 12 times in ClinVar: three times as pathogenic, eight times as likely pathogenic, and once as uncertain significance (Variation ID: 200022). This variant has also been reported in multiple individuals with a clinical diagnosis of MFS, ectopia lentis and/or clinical features of MFS (PS4_Strong; PMID 32730690, 10533071, 30675029, internal lab data). This variant was found to segregate with disease in at least four affected relatives with MFS from four families (PMID 32730690, internal lab data; PP1_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3713A>G (p.Asp1238Gly), has previously been previously established as (likely) pathogenic and was reported an individual with a clinical diagnosis of MFS (PM5; PMID 11175294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.895). This variant is located in the last nucleotide of the exon. In silico prediction programs suggest a possibly impact on splicing, however RNA analysis using patient blood showed no impact for this variant on RNA splicing (PMID 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Strong, PM1, PM5, PP1_Mod, PM2_Sup, PP2, PP3, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA014476/MONDO:0007947/022

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:13 U:1
• Conservation: PhyloP100: 7.90
• Publications: 5 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: Pathogenic. The variant received 14 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.3712G>A	p.Asp1238Asn	missense_variant, splice_region_variant	Exon 30 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.3712G>A	p.Asp1238Asn	missense_variant, splice_region_variant	Exon 29 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.3712G>A	p.Asp1238Asn	missense_variant, splice_region_variant	Exon 30 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Marfan syndrome Pathogenic:5

Nov 07, 2017

Center for Medical Genetics Ghent, University of Ghent

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2018

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2024

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_00138 c.3712G>A is a missense variant in FBN1 predicted to cause a substitution of an aspartic acid by asparagine at amino acid 1238 (p.Asp1238Asn). This variant impacts the first aspartic acid within a calcium-binding (cb) (D/N)-X-(D/N)-(E/Q)-Xm-(D/N)-Xn-(Y/F) consensus sequence of a cbEGF-like domain (PM1). This variant was found in a proband with a clinical diagnosis of Marfan syndrome (MFS) (Internal lab data, PP4). This variant has been reported 12 times in ClinVar: three times as pathogenic, eight times as likely pathogenic, and once as uncertain significance (Variation ID: 200022). This variant has also been reported in multiple individuals with a clinical diagnosis of MFS, ectopia lentis and/or clinical features of MFS (PS4_Strong; PMID 32730690, 10533071, 30675029, internal lab data). This variant was found to segregate with disease in at least four affected relatives with MFS from four families (PMID 32730690, internal lab data; PP1_Mod). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). A different missense variant at this position, c.3713A>G (p.Asp1238Gly), has previously been previously established as (likely) pathogenic and was reported an individual with a clinical diagnosis of MFS (PM5; PMID 11175294). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (REVEL: 0.895). This variant is located in the last nucleotide of the exon. In silico prediction programs suggest a possibly impact on splicing, however RNA analysis using patient blood showed no impact for this variant on RNA splicing (PMID 32123317). The constraint z-score for missense variants affecting FBN1 is 5.06 (PP2). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PS4_Strong, PM1, PM5, PP1_Mod, PM2_Sup, PP2, PP3, PP4. -

Sep 04, 2024

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3

Dec 29, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1238N variant (also known as c.3712G>A), located in coding exon 29 of the FBN1 gene, results from a G to A substitution at nucleotide position 3712. The amino acid change results in aspartic acid to asparagine, an amino acid with highly similar properties at codon 1238. However, this change occurs in the last base pair of coding exon 29, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in numerous individuals with phenotypes consistent with a Marfan syndrome diagnosis, including segregating with disease in some families (Yuan B et al. Hum. Mutat., 1999;14:440-6; Renner S et al. Genet Med, 2019 08;21:1832-1841; Cope H et al. Mol Genet Genomic Med, 2020 10;8:e1397; external communication; Ambry internal data). This variant alters a conserved residue in the calcium-binding consensus sequence of a cbEGF domain and is expected to disrupt FBN1 function (Handford PA et al. Nature. 1991; 351(6322):164-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. In addition, as a missense substitution this is predicted to be inconclusive by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Apr 08, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces aspartate with asparagine at codon 1238 in calcium-binding EGF-like motif 20 (a.a. 1238-1279) of the FBN1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant alters the last nucleotide of the exon, which is part of the 5' splice region. Splice prediction tools are inconclusive regarding the impact of this variant on RNA splicing, while an RNA study has shown that this variant does not change RNA splicing (PMID: 3212331). This variant has been reported in five individuals affected with Marfan syndrome (PMID: 10533071, 30675029, 32730690, 38190127; ClinVar SCV000948948.6) and in two individuals affected with aortic aneurysms and dissections (PMID: 29510914, Color internal data). It has also been observed in an asymptomatic individual (PMID: 34135346). 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. -

not provided Pathogenic:3

Jul 03, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with Marfan syndrome and/or TAAD (PMID: 10533071, 30675029, 32730690); Not observed at significant frequency in large population cohorts (gnomAD); In vitro RT-PCR and transcriptome-wide blood RNA sequencing demonstrated that p.(D1238N) results in normal splicing (PMID: 32123317); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 20886638, 29510914, 30675029, 32730690, 34135346, 10533071, 20591885, 32123317, 38190127, 34663891, 36945115) -

Mar 22, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2017

Blueprint Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1238 of the FBN1 protein (p.Asp1238Asn). This variant also falls at the last nucleotide of exon 30, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 10533071; internal data). ClinVar contains an entry for this variant (Variation ID: 200022). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -

Marfan syndrome;C0265287:Acromicric dysplasia;C1858556:MASS syndrome;C1861456:Stiff skin syndrome;C1869115:Weill-Marchesani syndrome 2, dominant;C3280054:Geleophysic dysplasia 2;C3541518:Ectopia lentis 1, isolated, autosomal dominant;C4310796:Progeroid and marfanoid aspect-lipodystrophy syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Oct 08, 2019

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.3712G>A (p.Asp1238Asn) results in a conservative amino acid change located in the EGF-like domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is located at the last 3' position of exon 30, therefore, suggesting the variant could affect splicing. Several computational tools predict a suggestive impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251466 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3712G>A has been reported in the literature in individuals affected with Marfan Syndrome and aortopathies and related disorders of connective tissue (De Cario_2018, Yuan_1999, Renner_2019). Hicks_2018 reports a 15 y/o female that presented with no phenotypic representation, however, had a family history. These report(s) 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. However, HGMD reports another missense variant at this location, D1238N, associated with Marfan syndrome. Seven ClinVar submissions (evaluation after 2014) cites the variant three times as pathogenic, three times as likely pathogenic, and once 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	0.95
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	36
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.016	D
Vest4		0.85
MutPred		0.90		Loss of phosphorylation at T1237 (P = 0.1426);
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.9
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		1.0
SpliceAI score (max)		0.54		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs794728208; hg19: chr15-48777571;