NM_001999.4(FBN2):c.489C>G (p.His163Gln) AND Congenital contractural arachnodactyly

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 2, 2022
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:: RCV002272918.3

Allele description [Variation Report for NM_001999.4(FBN2):c.489C>G (p.His163Gln)]

NM_001999.4(FBN2):c.489C>G (p.His163Gln)

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.489C>G (p.His163Gln)

HGVS:

NC_000005.10:g.128527915G>C
NG_008750.1:g.15128C>G
NM_001999.4:c.489C>GMANE SELECT
NP_001990.2:p.His163Gln
NC_000005.9:g.127863608G>C
NM_001999.3:c.489C>G

Protein change:

H163Q

Links:

dbSNP: rs2112798145

NCBI 1000 Genomes Browser:

rs2112798145

Molecular consequence:

NM_001999.4:c.489C>G - 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
SCV002557382	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31316167, 33571691, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557382

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A clinical scoring system for congenital contractural arachnodactyly.

Meerschaut I, De Coninck S, Steyaert W, Barnicoat A, Bayat A, Benedicenti F, Berland S, Blair EM, Breckpot J, de Burca A, Destrée A, García-Miñaúr S, Green AJ, Hanna BC, Keymolen K, Koopmans M, Lederer D, Lees M, Longman C, Lynch SA, Male AM, McKenzie F, et al.

Genet Med. 2020 Jan;22(1):124-131. doi: 10.1038/s41436-019-0609-8. Epub 2019 Jul 18.

PubMed [citation]

PMID:: 31316167

Severe congenital contractural arachnodactyly caused by biallelic pathogenic variants in FBN2.

Kloth K, Neu A, Rau I, Hülsemann W, Kutsche K, Volk AE.

Eur J Med Genet. 2021 Mar;64(3):104161. doi: 10.1016/j.ejmg.2021.104161. Epub 2021 Feb 9.

PubMed [citation]

PMID:: 33571691

See all PubMed Citations (3)

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557382.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, dominant negative is a likely mechanism of disease (PMID: 31316167). (I) 0107 - This gene is associated with autosomal dominant disease. There are also rare reports of a severe form of congenital contractural arachnodactyly due to biallelic variants (PMID: 33571691). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and inter-familial variability is well-reported for this gene (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Two alternative amino acid changes at the same position has been observed in gnomAD (v2) (p.(His163Arg): 3 heterozygotes, 0 homozygotes); (p.(His163Leu): 1 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(His163Arg) variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 23, 2024

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