NM_000138.5(FBN1):c.6163+1G>A AND Marfan syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 10, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004004228.2

Allele description [Variation Report for NM_000138.5(FBN1):c.6163+1G>A]

NM_000138.5(FBN1):c.6163+1G>A

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.6163+1G>A

HGVS:

NC_000015.10:g.48441720C>T
NG_008805.2:g.209069G>A
NM_000138.5:c.6163+1G>AMANE SELECT
NM_001406716.1:c.6163+1G>A
LRG_778t1:c.6163+1G>A
LRG_778:g.209069G>A
NC_000015.9:g.48733917C>T
NM_000138.4:c.6163+1G>A

Links:

dbSNP: rs1566897374

NCBI 1000 Genomes Browser:

rs1566897374

Molecular consequence:

NM_000138.5:c.6163+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406716.1:c.6163+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004825082	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 16199547, 16220557, 17657824, 17701892, 19293843, 21063442, 25613431, 25907466, 30286810, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004825082

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Nov 10, 2023)

germline

clinical testing

PubMed (10)
[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	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Identification of 29 novel and nine recurrent fibrillin-1 (FBN1) mutations and genotype-phenotype correlations in 76 patients with Marfan syndrome.

Rommel K, Karck M, Haverich A, von Kodolitsch Y, Rybczynski M, Müller G, Singh KK, Schmidtke J, Arslan-Kirchner M.

Hum Mutat. 2005 Dec;26(6):529-39.

PubMed [citation]

PMID:: 16220557

See all PubMed Citations (10)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004825082.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

The c.6163+1G>A variant in the FBN1 gene affects the canonical donor splice site of intron 50. This variant has not been reported in individuals with FBN1 related conditions in the literature. In-silico computational prediction tools predict that the c.6163+1G>A variant likely leads to donor loss (Splice AI: 0.9299) and disturbs normal splicing, resulting in an aberrant or absence of protein product (PMID: 16199547). Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17701892, 30286810, 21063442, 17657824, 19293843). Loss of function variants downstream of this variant are reported to be pathogenic in the literature (PMID:16220557, 25613431, 25907466). This variant is found to be absent in the general population databas (gnomAD) and interpreted as likely pathogenic by one submitter in the ClinVar database (ClinVar ID: 565539). Therefore, the c.6163+1G>A variant in the FBN1 gene is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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