NM_001999.4(FBN2):c.6122G>A (p.Cys2041Tyr) AND Congenital contractural arachnodactyly

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 27, 2020
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:: RCV001378653.6

Allele description

NM_001999.4(FBN2):c.6122G>A (p.Cys2041Tyr)

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.6122G>A (p.Cys2041Tyr)

HGVS:

NC_000005.10:g.128300861C>T
NG_008750.1:g.242183G>A
NM_001999.4:c.6122G>AMANE SELECT
NP_001990.2:p.Cys2041Tyr
NC_000005.9:g.127636553C>T

Protein change:

C2041Y

Links:

dbSNP: rs2126833724

NCBI 1000 Genomes Browser:

rs2126833724

Molecular consequence:

NM_001999.4:c.6122G>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
SCV001576269	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001576269

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 27, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV001576269.4

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

Description

This variant has been observed in individual(s) with clinical features of congenital contractural arachnodactyly (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 2041 of the FBN2 protein (p.Cys2041Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine.

#	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: Mar 5, 2024

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