VCV002734777.1 - ClinVar

NM_001999.4(FBN2):c.4273T>C (p.Cys1425Arg)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001999.4(FBN2):c.4273T>C (p.Cys1425Arg)

Variation ID: 2734777 Accession: VCV002734777.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 5q23.3 5: 128330645 (GRCh38) [ NCBI UCSC ] 5: 127666337 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 14, 2024	Feb 14, 2024	Nov 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001999.4:c.4273T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001990.2:p.Cys1425Arg	missense
NC_000005.10:g.128330645A>G
NC_000005.9:g.127666337A>G
NG_008750.1:g.212399T>C
NG_008750.2:g.212600T>C

... more HGVS ... less HGVS

Protein change

C1425R

Other names

Canonical SPDI

NC_000005.10:128330644:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FBN2		No evidence available	No evidence available	GRCh38 GRCh37	3126	3246

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital contractural arachnodactyly	Pathogenic (1)	criteria provided, single submitter	Nov 1, 2023	RCV003527201.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 01, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Congenital contractural arachnodactyly Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004292837.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 19006240‚ 3495735‚ 4750422‚ 16677079‚ 18767143 Comment: This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1425 of the FBN2 protein … (more) This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1425 of the FBN2 protein (p.Cys1425Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital contractural arachnodactyly (PMID: 19006240). 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 with a positive predictive value of 80%. 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. (less)

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1425 of the FBN2 protein (p.Cys1425Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital contractural arachnodactyly (PMID: 19006240). 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 with a positive predictive value of 80%. 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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature.	Callewaert BL	Human mutation	2009	PMID: 19006240
The FBN2 gene: new mutations, locus-specific database (Universal Mutation Database FBN2), and genotype-phenotype correlations.	Frédéric MY	Human mutation	2009	PMID: 18767143
Fibrillin-1 misfolding and disease.	Whiteman P	Antioxidants & redox signaling	2006	PMID: 16677079
The solution structure of human epidermal growth factor.	Cooke RM	Nature	1987	PMID: 3495735
Epidermal growth factor. Location of disulfide bonds.	Savage CR Jr	The Journal of biological chemistry	1973	PMID: 4750422

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001999.4(FBN2):c.4273T>C (p.Cys1425Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...