NM_000138.5(FBN1):c.2056G>A (p.Ala686Thr) AND Marfan syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 1, 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:: RCV000148498.4

Allele description [Variation Report for NM_000138.5(FBN1):c.2056G>A (p.Ala686Thr)]

NM_000138.5(FBN1):c.2056G>A (p.Ala686Thr)

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.2056G>A (p.Ala686Thr)

HGVS:

NC_000015.10:g.48503844C>T
NG_008805.2:g.146945G>A
NM_000138.5:c.2056G>AMANE SELECT
NP_000129.3:p.Ala686Thr
NP_000129.3:p.Ala686Thr
LRG_778t1:c.2056G>A
LRG_778:g.146945G>A
LRG_778p1:p.Ala686Thr
NC_000015.9:g.48796041C>T
NM_000138.4:c.2056G>A

Protein change:

A686T

Links:

dbSNP: rs377621293

NCBI 1000 Genomes Browser:

rs377621293

Molecular consequence:

NM_000138.5:c.2056G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000190207	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV004814926	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24199744, 28855619, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190207

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV004814926

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 1, 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	unknown	2	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Detection of 15 novel mutations in 52 children from 40 families with the Marfan or Loeys-Dietz syndrome and phenotype-genotype correlations.

Pees C, Michel-Behnke I, Hagl M, Laccone F.

Clin Genet. 2014 Dec;86(6):552-7. doi: 10.1111/cge.12314. Epub 2013 Dec 4.

PubMed [citation]

PMID:: 24199744

Identification of Novel Clinically Relevant Variants in 70 Southern Chinese patients with Thoracic Aortic Aneurysm and Dissection by Next-generation Sequencing.

Fang M, Yu C, Chen S, Xiong W, Li X, Zeng R, Zhuang J, Fan R.

Sci Rep. 2017 Aug 30;7(1):10035. doi: 10.1038/s41598-017-09785-y.

PubMed [citation]

PMID:: 28855619
PMCID:: PMC5577253

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190207.1

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

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

From All of Us Research Program, National Institutes of Health, SCV004814926.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces alanine with threonine at codon 686 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with severe Marfan or Loeys-Dietz syndrome with cardiac involvement (PMID: 24199744) and in an individual affected with thoracic aortic aneurysm and dissection (PMID: 28855619). This variant has also been identified in 20/282852 chromosomes (15/19952 East Asian 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: May 7, 2024

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