The 5788+5G>A variant has been previously reported in >15 individuals with a cli nical diagnosis or features of Marfan syndrome, and was reported to have occurre d de novo in >10 of these individuals (Nijbroek 1995, Yuan 1999, Loeys 2001, Com eglio 2007, Rommel 2002, Biggin 2004, Arbustini 2005, Sakai 2006, Rand-Hendrikse n 2007, Stheneur 2009, Soylen 2009, Baetens 2011, Aalberts 2014, LMM unpublished data). This variant was absent from large population studies. This variant occu rs in the highly conserved 5' splicing consensus sequence. Nijbroek et al. (1995 ) observed skipping of exon 46 in fibroblasts from an affected individual with t his variant, which is predicted to result in an abnormal protein product. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM).
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic/Likely pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 16
- First in ClinVar:
- Oct 9, 2016
- Most recent Submission:
- Nov 11, 2023
- Last evaluated:
- Jan 16, 2023
- Accession:
- VCV000042394.61
- Variation ID:
- 42394
- Description:
- single nucleotide variant
Help
NM_000138.5(FBN1):c.5788+5G>A
- Allele ID
- 51564
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 15q21.1
- Genomic location
- 15: 48446701 (GRCh38) GRCh38 UCSC
- 15: 48738898 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000138.5:c.5788+5G>A MANE Select intron variant NC_000015.10:g.48446701C>T NC_000015.9:g.48738898C>T NG_008805.2:g.204088G>A LRG_778:g.204088G>A LRG_778t1:c.5788+5G>A - Protein change
- -
- Other names
- IVS46+5G-A
- Canonical SPDI
- NC_000015.10:48446700:C:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- The Genome Aggregation Database (gnomAD) 0.00001
- Trans-Omics for Precision Medicine (TOPMed) 0.00000
- Links
- dbSNP: rs193922219
- ClinGen: CA016065
- OMIM: 134797.0039
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic/Likely pathogenic | 8 | criteria provided, multiple submitters, no conflicts | Feb 2, 2022 | RCV000035236.14 | |
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Apr 1, 2022 | RCV000181550.11 | |
| Pathogenic | 1 | no assertion criteria provided | May 25, 2016 | RCV000415118.5 | |
| Pathogenic | 1 | criteria provided, single submitter | Apr 18, 2022 | RCV000684778.8 | |
| Pathogenic | 1 | criteria provided, single submitter | Jan 16, 2023 | RCV000781375.7 | |
| Pathogenic | 2 | criteria provided, multiple submitters, no conflicts | Jul 31, 2020 | RCV001170536.6 | |
| Pathogenic | 1 | criteria provided, single submitter | Dec 8, 2021 | RCV002287351.4 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| FBN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
6336 | 6619 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781389.1
First in ClinVar: Feb 15, 2018 Last updated: Feb 15, 2018 |
|
|
|
Pathogenic
(Feb 17, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000058881.5
First in ClinVar: May 03, 2013 Last updated: Feb 15, 2018 |
Comment:
The 5788+5G>A variant has been previously reported in >15 individuals with a cli nical diagnosis or features of Marfan syndrome, and was reported to have … (more)
The 5788+5G>A variant has been previously reported in >15 individuals with a cli nical diagnosis or features of Marfan syndrome, and was reported to have occurre d de novo in >10 of these individuals (Nijbroek 1995, Yuan 1999, Loeys 2001, Com eglio 2007, Rommel 2002, Biggin 2004, Arbustini 2005, Sakai 2006, Rand-Hendrikse n 2007, Stheneur 2009, Soylen 2009, Baetens 2011, Aalberts 2014, LMM unpublished data). This variant was absent from large population studies. This variant occu rs in the highly conserved 5' splicing consensus sequence. Nijbroek et al. (1995 ) observed skipping of exon 46 in fibroblasts from an affected individual with t his variant, which is predicted to result in an abnormal protein product. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp gm.partners.org/LMM). (less)
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Feb 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV001333121.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
|
|
|
Likely pathogenic
(Mar 01, 2021)
|
criteria provided, single submitter
Method: research
|
Affected status: yes
Allele origin:
unknown
|
Centre of Medical Genetics, University of Antwerp
Accession: SCV002025358.1
First in ClinVar: May 24, 2022 Last updated: May 24, 2022 |
Comment:
PM2, PS1, PP1, PP4 and PM2, PS1, PP4
Number of individuals with the variant: 4
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics
Accession: SCV002097020.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Jul 31, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002652158.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.5788+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides downstream of coding exon 46 in the FBN1 gene. This mutation … (more)
The c.5788+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides downstream of coding exon 46 in the FBN1 gene. This mutation (also referred to as IVS 46+5G>A) was first described in three unrelated patients (two of whom were reported as de novo) with classic Marfan syndrome (MFS), and was shown to cause exon 46 skipping by mRNA analysis using cultured skin fibroblasts from one patient (Nijbroek G et al, Am. J. Hum. Genet. 1995 Jul; 57(1):8-21). This mutation has also been described in multiple additional patients with MFS with additional reported de novo occurrences (Loeys B et al, Arch. Intern. Med. 2001 Nov; 161(20):2447-54; Rommel K et al, Hum. Mutat. 2002 Nov; 20(5):406-7; Arbustini E et al, Hum. Mutat. 2005 Nov; 26(5):494; Sakai H et al, Am. J. Med. Genet. A 2006 Aug; 140(16):1719-25; Rand-Hendriksen S et al, Am. J. Med. Genet. A 2007 Sep; 143A(17):1968-77; Söylen B et al, Clin. Genet. 2009 Mar; 75(3):265-70; Baetens M et al, Hum. Mutat. 2011 Sep; 32(9):1053-62; Li J et al. Sci China Life Sci. 2019;62(12):1630-1637). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447220.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Abnormality of body height (present) , Aortic dissection (present) , Lens subluxation (present)
Sex: male
|
|
|
Pathogenic
(Dec 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University Hospital Muenster
Accession: SCV002577777.1
First in ClinVar: Oct 08, 2022 Last updated: Oct 08, 2022 |
Comment:
ACMG categories: PS2,PM2,PP3,PP5
Number of individuals with the variant: 1
Clinical Features:
Disproportionate tall stature (present) , Abnormality of connective tissue (present)
Zygosity: 1 Single Heterozygote
Age: 0-9 years
Sex: male
Tissue: blood
|
|
|
Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768078.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are also associated with causing Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; however some individuals have been reported with an autosomal recessive form of Marfan syndrome (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with the same variant reported in patients with a range of phenotypes (OMIM). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RT-PCR analysis of cultured fibroblasts from an affected individual showed that the variant causes in-frame skipping of exon 47 and a small amount of abnormally spliced transcripts utilized a cryptic splice donor or a cryptic splice acceptor (PMID: 7611299). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.5788+5G>T variant has been observed in an individual with Marfan syndrome and classified as likely pathogenic (VCGS laboratory). This variant has also been reported twice as a VUS in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Marfan syndrome (ClinVar, PMID: 7611299, PMID: 24161884). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Apr 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000283640.7
First in ClinVar: Jul 01, 2016 Last updated: Feb 07, 2023 |
Comment:
This sequence change falls in intron 47 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. … (more)
This sequence change falls in intron 47 of the FBN1 gene. It does not directly change the encoded amino acid sequence of the FBN1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Marfan syndrome (PMID: 7611299, 11700157, 12402346, 14695540, 17657824, 17663468). In at least one individual the variant was observed to be de novo. This variant is also known as IVS46+5G>A. ClinVar contains an entry for this variant (Variation ID: 42394). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 46, but is expected to preserve the integrity of the reading-frame (PMID: 7611299). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919354.3
First in ClinVar: Jun 03, 2019 Last updated: Nov 11, 2023 |
Comment:
Variant summary: FBN1 c.5788+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: FBN1 c.5788+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. One predicts the variant weakens the canonical 5' splicing donor site. Two publications report experimental evidence suggesting that this variant causes skipping of exon 46 (Liu_1996; Nijbroek_1995). The variant was absent in 251390 control chromosomes. c.5788+5G>A has been reported in the literature in multiple individuals affected with Marfan Syndrome (example, Baetens_2011, Liu_1996, Nijbroek_1995, Rand-Hendriksen_2007, Stheneur_2009). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Apr 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233853.14
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies showed RT-PCR performed on fibroblasts from individuals harboring this variant revealed c.5788+5 G>A leads to in-frame skipping of the preceding exon (Nijbroek … (more)
Published functional studies showed RT-PCR performed on fibroblasts from individuals harboring this variant revealed c.5788+5 G>A leads to in-frame skipping of the preceding exon (Nijbroek et al., 1995; Lui et al., 1996; Wai et al., 2020).; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 42394; ClinVar); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 19293843, 11700157, 21542060, 14695540, 24161884, 8894692, 34818515, 34550612, 34498425, 7611299, 25525159, 17657824, 10533071, 12402346, 16835936, 17663468, 19159394, 33174221, 33083483, 31098894, 31730815, 16220557, 32123317, 16222657, 26582918) (less)
|
|
|
Pathogenic
(Sep 01, 2003)
|
no assertion criteria provided
Method: literature only
|
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038200.3
First in ClinVar: Apr 04, 2013 Last updated: Jan 06, 2017 |
Comment on evidence:
In patients with Marfan syndrome (154700), Nijbroek et al. (1995) and Liu et al. (1996) reported skipping of exon 46 of the FBN1 gene due … (more)
In patients with Marfan syndrome (154700), Nijbroek et al. (1995) and Liu et al. (1996) reported skipping of exon 46 of the FBN1 gene due to a G-to-A transversion at the +5 position of the consensus 5-prime splice site. Collod-Beroud et al. (2003) noted that this mutation was the most frequently recurring mutation to that time, having been reported a total of 9 times. (less)
|
|
|
Likely pathogenic
(Nov 07, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
germline
|
Center for Medical Genetics Ghent, University of Ghent
Accession: SCV000787173.1
First in ClinVar: Jul 21, 2018 Last updated: Jul 21, 2018 |
|
|
|
Pathogenic
(May 25, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492582.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
|
|
|
Pathogenic
(Apr 10, 2023)
|
no assertion criteria provided
Method: case-control
|
Affected status: yes
Allele origin:
germline
|
deCODE genetics, Amgen
Accession: SCV003915950.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
The c.5788+5G>A variant occurred de novo in two siblings (shared de novo) with Marfan syndrome, maternity and paternity confirmed, parental mosaicism assumed. Applied ACMG criteria: … (more)
The c.5788+5G>A variant occurred de novo in two siblings (shared de novo) with Marfan syndrome, maternity and paternity confirmed, parental mosaicism assumed. Applied ACMG criteria: PS2, PM2, PP2, PP4, PP5_strong (less)
Number of individuals with the variant: 2
Ethnicity/Population group: Icelandic
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A population-based survey of FBN1 variants in Iceland reveals underdiagnosis of Marfan syndrome. | Klemenzdottir EO | European journal of human genetics : EJHG | 2023 | PMID: 37684520 |
| Application of next-generation sequencing to screen for pathogenic mutations in 123 unrelated Chinese patients with Marfan syndrome or a related disease. | Li J | Science China. Life sciences | 2019 | PMID: 31098894 |
| The importance of genotype-phenotype correlation in the clinical management of Marfan syndrome. | Becerra-Muñoz VM | Orphanet journal of rare diseases | 2018 | PMID: 29357934 |
| Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. | Nykamp K | Genetics in medicine : official journal of the American College of Medical Genetics | 2017 | PMID: 28492532 |
| Aortic dilation, genetic testing, and associated diagnoses. | Zarate YA | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26133393 |
| Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome. | Aalberts JJ | Gene | 2014 | PMID: 24161884 |
| Applying massive parallel sequencing to molecular diagnosis of Marfan and Loeys-Dietz syndromes. | Baetens M | Human mutation | 2011 | PMID: 21542060 |
| Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. | Stheneur C | European journal of human genetics : EJHG | 2009 | PMID: 19293843 |
| Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. | Söylen B | Clinical genetics | 2009 | PMID: 19159394 |
| Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. | Rand-Hendriksen S | American journal of medical genetics. Part A | 2007 | PMID: 17663468 |
| The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. | Comeglio P | Human mutation | 2007 | PMID: 17657824 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. | Tjeldhorn L | Genetic testing | 2006 | PMID: 17253931 |
| Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. | Sakai H | American journal of medical genetics. Part A | 2006 | PMID: 16835936 |
| Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies. | Arbustini E | Human mutation | 2005 | PMID: 16222657 |
| Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome. | Rommel K | Human mutation | 2005 | PMID: 16220557 |
| Detection of thirty novel FBN1 mutations in patients with Marfan syndrome or a related fibrillinopathy. | Biggin A | Human mutation | 2004 | PMID: 14695540 |
| Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. | Collod-Béroud G | Human mutation | 2003 | PMID: 12938084 |
| Mutation screening of the fibrillin-1 (FBN1) gene in 76 unrelated patients with Marfan syndrome or Marfanoid features leads to the identification of 11 novel and three previously reported mutations. | Rommel K | Human mutation | 2002 | PMID: 12402346 |
| Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. | Loeys B | Archives of internal medicine | 2001 | PMID: 11700157 |
| Enzymatic mutation detection (EMD) of novel mutations (R565X and R1523X) in the FBN1 gene of patients with Marfan syndrome using T4 endonuclease VII. | Youil R | Human mutation | 2000 | PMID: 10874320 |
| Comparison of heteroduplex analysis, direct sequencing, and enzyme mismatch cleavage for detecting mutations in a large gene, FBN1. | Yuan B | Human mutation | 1999 | PMID: 10533071 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. | Hayward C | Human mutation | 1997 | PMID: 9401003 |
| Mutant fibrillin-1 monomers lacking EGF-like domains disrupt microfibril assembly and cause severe marfan syndrome. | Liu W | Human molecular genetics | 1996 | PMID: 8894692 |
| Fifteen novel FBN1 mutations causing Marfan syndrome detected by heteroduplex analysis of genomic amplicons. | Nijbroek G | American journal of human genetics | 1995 | PMID: 7611299 |
Text-mined citations for rs193922219...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 11, 2023