NM_000138.5(FBN1):c.6322C>T (p.Arg2108Cys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 14, 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:: RCV001069594.8

Allele description [Variation Report for NM_000138.5(FBN1):c.6322C>T (p.Arg2108Cys)]

NM_000138.5(FBN1):c.6322C>T (p.Arg2108Cys)

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.6322C>T (p.Arg2108Cys)

HGVS:

NC_000015.10:g.48437379G>A
NG_008805.2:g.213410C>T
NM_000138.5:c.6322C>TMANE SELECT
NP_000129.3:p.Arg2108Cys
NP_000129.3:p.Arg2108Cys
LRG_778t1:c.6322C>T
LRG_778:g.213410C>T
LRG_778p1:p.Arg2108Cys
NC_000015.9:g.48729576G>A
NM_000138.4:c.6322C>T

Protein change:

R2108C

Links:

dbSNP: rs1246984265

NCBI 1000 Genomes Browser:

rs1246984265

Molecular consequence:

NM_000138.5:c.6322C>T - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001234772	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 14, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27906200, 34550612, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001234772

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 14, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases.

Groth KA, Von Kodolitsch Y, Kutsche K, Gaustadnes M, Thorsen K, Andersen NH, Gravholt CH.

Genet Med. 2017 Jul;19(7):772-777. doi: 10.1038/gim.2016.181. Epub 2016 Dec 1.

PubMed [citation]

PMID:: 27906200

Correlation between FBN1 mutations and ocular features with ectopia lentis in the setting of Marfan syndrome and related fibrillinopathies.

Chen ZX, Chen TH, Zhang M, Chen JH, Lan LN, Deng M, Zheng JL, Jiang YX.

Hum Mutat. 2021 Dec;42(12):1637-1647. doi: 10.1002/humu.24283. Epub 2021 Sep 28.

PubMed [citation]

PMID:: 34550612

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234772.6

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBN1 protein function. ClinVar contains an entry for this variant (Variation ID: 549339). This missense change has been observed in individuals with clinical features of FBN1-related conditions (PMID: 27906200, 34550612; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2108 of the FBN1 protein (p.Arg2108Cys).

#	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: Apr 7, 2025

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