NM_000138.5(FBN1):c.5582G>A (p.Ser1861Asn) AND Marfan syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 28, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001095722.6

Allele description [Variation Report for NM_000138.5(FBN1):c.5582G>A (p.Ser1861Asn)]

NM_000138.5(FBN1):c.5582G>A (p.Ser1861Asn)

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.5582G>A (p.Ser1861Asn)

HGVS:

NC_000015.10:g.48448857C>T
NG_008805.2:g.201932G>A
NM_000138.5:c.5582G>AMANE SELECT
NP_000129.3:p.Ser1861Asn
NP_000129.3:p.Ser1861Asn
LRG_778t1:c.5582G>A
LRG_778:g.201932G>A
LRG_778p1:p.Ser1861Asn
NC_000015.9:g.48741054C>T
NM_000138.4:c.5582G>A

Protein change:

S1861N

Links:

dbSNP: rs766358553

NCBI 1000 Genomes Browser:

rs766358553

Molecular consequence:

NM_000138.5:c.5582G>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
SCV001251560	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Uncertain significance (Jan 22, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004814646	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31163209, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001251560

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Uncertain significance
(Jan 22, 2020)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004814646

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 28, 2023)

germline

clinical testing

PubMed (2)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

FBN1 gene mutations in 26 Hungarian patients with suspected Marfan syndrome or related fibrillinopathies.

Madar L, Szakszon K, Pfliegler G, Szabó GP, Brúgós B, Ronen N, Papp J, Zahuczky K, Szakos E, Fekete G, Oláh É, Koczok K, Balogh I.

J Biotechnol. 2019 Aug 10;301:105-111. doi: 10.1016/j.jbiotec.2019.05.012. Epub 2019 Jun 1.

PubMed [citation]

PMID:: 31163209

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001251560.2

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

Description

The FBN1 c.5582G>A (p.Ser1861Asn) variant is a missense variant that has been reported in one study in which it was identified in a heterozygous state in one individual suspected of having Marfan syndrome but with insufficient clinical evidence for a confirmed diagnosis (Madar et al. 2019). The p.Ser1861Asn variant is reported at a frequency of 0.000026 in the European (non-Finnish) population of the Genome Aggregation Database. The Ser1861 residue is located in one of the 47 calcium-binding EGF-like domains of the fibrillin-1 protein. Based on the limited evidence, the p.Ser1861Asn variant is classified as a variant of unknown significance for Marfan syndrome.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV004814646.1

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

Description

This missense variant replaces serine with asparagine at codon 1861 of the FBN1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with suspected Marfan syndrome or related fibrillinopathy (PMID: 31163209). This variant has also been identified in 4/250868 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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