NM_000138.5(FBN1):c.6872-14A>G AND Marfan syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 30, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000663907.11

Allele description [Variation Report for NM_000138.5(FBN1):c.6872-14A>G]

NM_000138.5(FBN1):c.6872-14A>G

Gene:

FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_000138.5(FBN1):c.6872-14A>G

HGVS:

NC_000015.10:g.48428485T>C
NG_008805.2:g.222304A>G
NM_000138.5:c.6872-14A>GMANE SELECT
LRG_778t1:c.6872-14A>G
LRG_778:g.222304A>G
NC_000015.9:g.48720682T>C
NM_000138.4:c.6872-14A>G

Links:

dbSNP: rs1064793119

NCBI 1000 Genomes Browser:

rs1064793119

Molecular consequence:

NM_000138.5:c.6872-14A>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

Recent activity

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Homo sapiens solute carrier family 25, member 26 (SLC25A26), transcript variant ...
Homo sapiens solute carrier family 25, member 26 (SLC25A26), transcript variant 2, mRNA
gi|27735034|ref|NM_173471.1|

Nucleotide
Gene neighbors for Gene (Select 117240) (12)
Gene
PREDICTED: Rattus norvegicus hephaestin (Heph), transcript variant X3, mRNA
PREDICTED: Rattus norvegicus hephaestin (Heph), transcript variant X3, mRNA
gi|2678974830|ref|XM_039099424.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000787274	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Uncertain significance (Nov 7, 2017)	de novo	clinical testing
SCV002025421	Centre of Medical Genetics, University of Antwerp	criteria provided, single submitter (Submitter's publication)	Uncertain significance (Mar 1, 2021)	unknown	research	Citation Link,
SCV002498630	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25907466, 29510914, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000787274

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Uncertain significance
(Nov 7, 2017)

de novo

clinical testing

SCV002025421

Centre of Medical Genetics, University of Antwerp

criteria provided, single submitter

(Submitter's publication)

Uncertain significance
(Mar 1, 2021)

unknown

research

Citation Link,

SCV002498630

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 30, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	de novo	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	2	1	not provided	not provided	not provided	research

Citations

PubMed

Performant Mutation Identification Using Targeted Next-Generation Sequencing of 14 Thoracic Aortic Aneurysm Genes.

Proost D, Vandeweyer G, Meester JA, Salemink S, Kempers M, Ingram C, Peeters N, Saenen J, Vrints C, Lacro RV, Roden D, Wuyts W, Dietz HC, Mortier G, Loeys BL, Van Laer L.

Hum Mutat. 2015 Aug;36(8):808-14. doi: 10.1002/humu.22802. Epub 2015 Jun 13.

PubMed [citation]

PMID:: 25907466

Testing patterns for genetically triggered aortic and arterial aneurysms and dissections at an academic center.

Hicks KL, Byers PH, Quiroga E, Pepin MG, Shalhub S.

J Vasc Surg. 2018 Sep;68(3):701-711. doi: 10.1016/j.jvs.2017.12.023. Epub 2018 Mar 3.

PubMed [citation]

PMID:: 29510914

See all PubMed Citations (3)

Details of each submission

From Center for Medical Genetics Ghent, University of Ghent, SCV000787274.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre of Medical Genetics, University of Antwerp, SCV002025421.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	not provided

Description

PM2, PP3, PP1, PP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		2	not provided	1	not provided

From Molecular Genetics, Royal Melbourne Hospital, SCV002498630.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change in FBN1 is an intronic variant located in intron 56. This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in at least two probands with a clinical diagnosis of Marfan syndrome and a proband with thoracic aortic aneurysm and aortic dissection (PMID: 25907466, 29510914; Royal Melbourne Hospital). It has also been identified as a de novo occurrence with unconfirmed parental relationships in an individual with Marfan syndrome (SCV000787274.1). The results from multiple in silico splicing predictors (SpliceAI, MaxEntScan, NNSplice) indicate that this variant may impact splicing by disrupting the acceptor splice site of intron 56 of FBN1 by gain of a de novo acceptor site upstream. This prediction is confirmed by RT-PCR of patient RNA. The assay demonstrated that the variant impacts splicing by use of a cryptic acceptor (unable to determine if complete/partial mis-splicing) within intron 56 (r.6871_6872ins[6872-13_6872-1]) resulting in a frameshift (p.Asp2291Valfs*6; RNA Diagnostics Kid's Neuroscience Centre) leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a LIKELY PATHOGENIC. Following criteria are met: PS3_Moderate, PS4_Moderate, PM2_Supporting, PM6_Supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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