NM_000138.5:c.247+2dupT

Variant names:

• chr15-48613007-T-TA
• rs397515772
• NM_000138.5:c.247+2dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000138.5(FBN1):​c.247+2dupT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN1 NM_000138.5 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.60
• Publications: 0 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 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-48613007-T-TA is Pathogenic according to our data. Variant chr15-48613007-T-TA is described in CliVar as Likely_pathogenic. Clinvar id is 42308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48613007-T-TA is described in CliVar as Likely_pathogenic. Clinvar id is 42308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48613007-T-TA is described in CliVar as Likely_pathogenic. Clinvar id is 42308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-48613007-T-TA is described in CliVar as Likely_pathogenic. Clinvar id is 42308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.247+2dupT		splice_donor_variant, intron_variant	Intron 3 of 65	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.247+2dupT		splice_donor_variant, intron_variant	Intron 2 of 64		NP_001393645.1
FBN1	NM_001406717.1	c.247+2dupT		splice_donor_variant, intron_variant	Intron 3 of 8		NP_001393646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 65	1	NM_000138.5	ENSP00000325527.5
FBN1	ENST00000559133.6	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 66	1		ENSP00000453958.2
FBN1	ENST00000537463.6	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 30	5		ENSP00000440294.2
FBN1	ENST00000674301.2	n.247+2_247+3insT		splice_donor_variant, intron_variant	Intron 3 of 67			ENSP00000501333.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Marfan syndrome Pathogenic:1

Oct 08, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247+2dup variant in FBN1 has been previously reported in two individuals with clinical features of Marfan syndrome and segregated with disease in one affected relative (Stheneur 2009 PMID: 19293843, LMM unpublished data). In one of these individuals, the variant was reportedly a de novo occurrence Stheneur 2009 PMID: PMID: 19293843). This variant was absent from large population databases. This variant is a duplication of the thymine (T) at nucleotide position c.247+2 and is predicted to disrupt the canonical splice site (+/- 1,2), leading to an abnormal or absent protein. Loss of function of the FBN1 gene is an established disease mechanism in autosomal dominant Marfan syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM6, PS4_Supporting. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 22, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.247+2dupT intronic variant is located 2 nucleotide(s) after coding exon 2 in the FBN1 gene. This variant results from a duplication of 1 nucleotide at position c.247+2. This variant does not change the sequence of the canonical donor at this splice site. This variant was reported in individual(s) with features consistent with Marfan syndrome; in at least one individual, it was determined to be de novo or the result of germline mosaicism (Stheneur C et al. Eur J Hum Genet, 2009 Sep;17:1121-8; Ambry internal data; external communication). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.6
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.44		Position offset: -1
DS_DL_spliceai		0.92		Position offset: 3

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

Other links and lift over

dbSNP: rs397515772; hg19: chr15-48905204;