NM_000138.5(FBN1):c.1510T>A (p.Cys504Ser) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 7, 2019
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:: RCV000808687.10

Allele description [Variation Report for NM_000138.5(FBN1):c.1510T>A (p.Cys504Ser)]

NM_000138.5(FBN1):c.1510T>A (p.Cys504Ser)

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.1510T>A (p.Cys504Ser)

HGVS:

NC_000015.10:g.48513627A>T
NG_008805.2:g.137162T>A
NM_000138.5:c.1510T>AMANE SELECT
NP_000129.3:p.Cys504Ser
NP_000129.3:p.Cys504Ser
LRG_778t1:c.1510T>A
LRG_778:g.137162T>A
LRG_778p1:p.Cys504Ser
NC_000015.9:g.48805824A>T
NM_000138.4:c.1510T>A

Protein change:

C504S

Links:

dbSNP: rs1555400288

NCBI 1000 Genomes Browser:

rs1555400288

Molecular consequence:

NM_000138.5:c.1510T>A - missense variant - [Sequence Ontology: SO:0001583]

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

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Mus musculus tigger transposable element derived 3 (Tigd3), transcript variant 2, mRNA
gi|1372261766|ref|NM_001362045.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000948802	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 7, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17657824, 10425041, 17627385, 16905551, 19349279, 16571647, 17701892, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000948802

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 7, 2019)

germline

clinical testing

PubMed (8)
[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	not provided	not provided	not provided	not provided	not provided	clinical 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

Identification of 9 novel FBN1 mutations in German patients with Marfan syndrome.

El-Aleem AA, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M.

Hum Mutat. 1999 Aug 19;14(2):181.

PubMed [citation]

PMID:: 10425041

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948802.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the¬†p.Cys504¬†amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 17657824, 10425041, 17627385), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant has not been reported in the literature in individuals with FBN1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 504 of the FBN1 protein (p.Cys504Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine.

#	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

Last Updated: Sep 29, 2024

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