NM_001999.4(FBN2):c.3593G>A (p.Cys1198Tyr) AND Congenital contractural arachnodactyly

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 23, 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:: RCV003525874.2

Allele description [Variation Report for NM_001999.4(FBN2):c.3593G>A (p.Cys1198Tyr)]

NM_001999.4(FBN2):c.3593G>A (p.Cys1198Tyr)

Gene:

FBN2:fibrillin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q23.3

Genomic location:

Preferred name:

NM_001999.4(FBN2):c.3593G>A (p.Cys1198Tyr)

HGVS:

NC_000005.10:g.128338002C>T
NG_008750.1:g.205042G>A
NM_001999.4:c.3593G>AMANE SELECT
NP_001990.2:p.Cys1198Tyr
NC_000005.9:g.127673694C>T
NM_001999.3:c.3593G>A
P35556:p.Cys1198Tyr
p.C1198Y

Protein change:

C1198Y

Links:

UniProtKB: P35556#VAR_054984; dbSNP: rs863223567

NCBI 1000 Genomes Browser:

rs863223567

Molecular consequence:

NM_001999.4:c.3593G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Congenital contractural arachnodactyly (CCA)
Synonyms:: Beals syndrome; Arachnodactyly, contractural Beals type; Contractures, multiple with arachnodactyly; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007363; MedGen: C0220668; Orphanet: 115; OMIM: 121050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004292841	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 23, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11754102, 3495735, 4750422, 16677079, 18767143, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004292841

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 23, 2023)

germline

clinical testing

PubMed (6)
[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

Ten novel FBN2 mutations in congenital contractural arachnodactyly: delineation of the molecular pathogenesis and clinical phenotype.

Gupta PA, Putnam EA, Carmical SG, Kaitila I, Steinmann B, Child A, Danesino C, Metcalfe K, Berry SA, Chen E, Delorme CV, Thong MK, Adès LC, Milewicz DM.

Hum Mutat. 2002 Jan;19(1):39-48.

PubMed [citation]

PMID:: 11754102

The solution structure of human epidermal growth factor.

Cooke RM, Wilkinson AJ, Baron M, Pastore A, Tappin MJ, Campbell ID, Gregory H, Sheard B.

Nature. 1987 May 28-Jun 3;327(6120):339-41.

PubMed [citation]

PMID:: 3495735

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV004292841.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense change has been observed in individual(s) with congenital contractural arachnodactyly (PMID: 11754102). ClinVar contains an entry for this variant (Variation ID: 213313). 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 FBN2 protein function. This variant affects a cysteine residue located within an epidermal growth factor (EGF)‚Äìlike domain of the FBN2 protein. Cysteine residues in these domains are involved in the formation of disulfide bridges critical for protein structure and stability (PMID: 3495735, 4750422, 16677079). In addition, missense substitutions within the FBN2 EGF-like domains affecting cysteine residues are overrepresented in patients with congenital contractural arachnodactyly (PMID: 18767143). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1198 of the FBN2 protein (p.Cys1198Tyr).

#	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: Jun 23, 2024

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