NM_000138.5(FBN1):c.8232G>C (p.Gln2744His) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 9, 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:: RCV001181857.6

Allele description [Variation Report for NM_000138.5(FBN1):c.8232G>C (p.Gln2744His)]

NM_000138.5(FBN1):c.8232G>C (p.Gln2744His)

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.8232G>C (p.Gln2744His)

HGVS:

NC_000015.10:g.48411374C>G
NG_008805.2:g.239415G>C
NM_000138.5:c.8232G>CMANE SELECT
NP_000129.3:p.Gln2744His
NP_000129.3:p.Gln2744His
LRG_778t1:c.8232G>C
LRG_778:g.239415G>C
LRG_778p1:p.Gln2744His
NC_000015.9:g.48703571C>G
NM_000138.4:c.8232G>C

Protein change:

Q2744H

Links:

dbSNP: rs376119827

NCBI 1000 Genomes Browser:

rs376119827

Molecular consequence:

NM_000138.5:c.8232G>C - 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
SCV001347099	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28659821, 29907982, 25741868
SCV002676139	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Mar 20, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001347099

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 9, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002676139

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Mar 20, 2020)

germline

clinical testing

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

Citation Link

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

Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor.

Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, Wieschendorf B, Alaerts M, Bolar N, Vandeweyer G, Meester J, Wünnemann F, Gould RA, Zhurayev R, Zerbino D, Mohamed SA, Mital S, Mertens L, Björck HM, Franco-Cereceda A, McCallion AS, Van Laer L, et al.

Front Physiol. 2017;8:400. doi: 10.3389/fphys.2017.00400. Erratum in: Front Physiol. 2017 Sep 25;8:730. doi: 10.3389/fphys.2017.00730.

PubMed [citation]

PMID:: 28659821
PMCID:: PMC5469151

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (3)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001347099.3

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

Description

This missense variant replaces glutamine with histidine at codon 2744 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and aortic dissection and/or bicuspid aortic valve (PMID: 28659821, 29907982). This variant has been identified in 3/250796 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 Ambry Genetics, SCV002676139.2

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

Description

The p.Q2744H variant (also known as c.8232G>C), located in coding exon 65 of the FBN1 gene, results from a G to C substitution at nucleotide position 8232. The glutamine at codon 2744 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a subject with carotid artery dissection, aortic aneurysm and pneumothorax (Overwater E et al. Hum. Mutat., 2018 09;39:1173-1192). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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: May 7, 2024

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