NM_000138.5(FBN1):c.4162C>T (p.Arg1388Cys) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001189586.5

Allele description [Variation Report for NM_000138.5(FBN1):c.4162C>T (p.Arg1388Cys)]

NM_000138.5(FBN1):c.4162C>T (p.Arg1388Cys)

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.4162C>T (p.Arg1388Cys)

Other names:

p.Arg1388Cys

HGVS:

NC_000015.10:g.48474303G>A
NG_008805.2:g.176486C>T
NM_000138.5:c.4162C>TMANE SELECT
NP_000129.3:p.Arg1388Cys
LRG_778t1:c.4162C>T
LRG_778:g.176486C>T
NC_000015.9:g.48766500G>A
NC_000015.9:g.48766500G>A
NM_000138.4:c.4162C>T

Protein change:

R1388C

Links:

dbSNP: rs770860280

NCBI 1000 Genomes Browser:

rs770860280

Molecular consequence:

NM_000138.5:c.4162C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001356897	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 24, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15161917, 16571647, 17701892, 34422331, 25741868
SCV004240574	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 16, 2023)	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

SCV001356897

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 24, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004240574

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 16, 2023)

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

Consequences of cysteine mutations in calcium-binding epidermal growth factor modules of fibrillin-1.

Vollbrandt T, Tiedemann K, El-Hallous E, Lin G, Brinckmann J, John H, Bätge B, Notbohm H, Reinhardt DP.

J Biol Chem. 2004 Jul 30;279(31):32924-31. Epub 2004 May 25.

PubMed [citation]

PMID:: 15161917

The molecular genetics of Marfan syndrome and related disorders.

Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, Kielty CM, Loeys B, Milewicz DM, Ney A, Ramirez F, Reinhardt DP, Tiedemann K, Whiteman P, Godfrey M.

J Med Genet. 2006 Oct;43(10):769-87. Epub 2006 Mar 29. Review.

PubMed [citation]

PMID:: 16571647
PMCID:: PMC2563177

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001356897.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant generates a cysteine residue in a calcium-binding EGF-like domain of the FBN1 protein. Cysteine creating variants in these domains have been shown to affect protein stability and are overrepresented among individuals with Marfan syndrome (PMID: 15161917, 16571647, 17701892). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in in individual affected with sporadic Stanford type A aortic dissection (PMID: 34422331). This variant has been identified in 1/251310 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV004240574.1

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

#	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: Oct 8, 2024

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