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NM_000138.5(FBN1):c.7660C>T (p.Arg2554Trp) AND Marfan syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Dec 18, 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:
RCV003998169.2

Allele description [Variation Report for NM_000138.5(FBN1):c.7660C>T (p.Arg2554Trp)]

NM_000138.5(FBN1):c.7660C>T (p.Arg2554Trp)

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.7660C>T (p.Arg2554Trp)
Other names:
p.R2554W:CGG>TGG
HGVS:
  • NC_000015.10:g.48421597G>A
  • NG_008805.2:g.229192C>T
  • NM_000138.5:c.7660C>TMANE SELECT
  • NP_000129.3:p.Arg2554Trp
  • NP_000129.3:p.Arg2554Trp
  • LRG_778t1:c.7660C>T
  • LRG_778:g.229192C>T
  • LRG_778p1:p.Arg2554Trp
  • NC_000015.9:g.48713794G>A
  • NM_000138.4:c.7660C>T
Protein change:
R2554W
Links:
dbSNP: rs369294972
NCBI 1000 Genomes Browser:
rs369294972
Molecular consequence:
  • NM_000138.5:c.7660C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
10

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004816749All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(Dec 18, 2023) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown10not providednot provided108544not providedclinical testing

Citations

PubMed

The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.

Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, da Silva FP, Kiotsekoglou A, Child A.

Hum Mutat. 2007 Sep;28(9):928.

PubMed [citation]
PMID:
17657824

De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

Priest JR, Osoegawa K, Mohammed N, Nanda V, Kundu R, Schultz K, Lammer EJ, Girirajan S, Scheetz T, Waggott D, Haddad F, Reddy S, Bernstein D, Burns T, Steimle JD, Yang XH, Moskowitz IP, Hurles M, Lifton RP, Nickerson D, Bamshad M, Eichler EE, et al.

PLoS Genet. 2016 Apr;12(4):e1005963. doi: 10.1371/journal.pgen.1005963.

PubMed [citation]
PMID:
27058611
PMCID:
PMC4825975
See all PubMed Citations (5)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004816749.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided10not providednot providedclinical testing PubMed (5)

Description

This missense variant replaces arginine with tryptophan at codon 2554 of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two related individuals affected with cervical artery dissection (PMID: 31008308, 31903434) and in three related individuals affected with atypical Marfan syndrome with major involvement of the cardiovascular system (PMID: 17657824). This variant has been reported in an individual affected with atrioventricular septal heart defect (PMID: 27058611). This variant has also been identified in 9/281700 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided10not providednot providednot provided

Last Updated: Oct 20, 2024