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NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 15, 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:
RCV000548224.15

Allele description [Variation Report for NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)]

NM_000138.5(FBN1):c.2920C>T (p.Arg974Cys)

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.2920C>T (p.Arg974Cys)
HGVS:
  • NC_000015.10:g.48490013G>A
  • NG_008805.2:g.160776C>T
  • NM_000138.5:c.2920C>TMANE SELECT
  • NP_000129.3:p.Arg974Cys
  • NP_000129.3:p.Arg974Cys
  • LRG_778t1:c.2920C>T
  • LRG_778:g.160776C>T
  • LRG_778p1:p.Arg974Cys
  • NC_000015.9:g.48782210G>A
  • NM_000138.4:c.2920C>T
Protein change:
R974C; ARG974CYS
Links:
OMIM: 134797.0063; dbSNP: rs397514558
NCBI 1000 Genomes Browser:
rs397514558
Molecular consequence:
  • NM_000138.5:c.2920C>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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000627874Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 15, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Application of dHPLC for mutation detection of the fibrillin-1 gene for the diagnosis of Marfan syndrome in a National Health Service Laboratory.

Howarth R, Yearwood C, Harvey JF.

Genet Test. 2007 Summer;11(2):146-52.

PubMed [citation]
PMID:
17627385

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
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627874.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 974 of the FBN1 protein (p.Arg974Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with isolated ectopia lentis and Marfan syndrome (PMID: 17627385, 17657824, 22539873). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 39667). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Dec 22, 2024