NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Feb 8, 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:: RCV002310746.10

Allele description [Variation Report for NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg)]

NM_000138.5(FBN1):c.2953G>A (p.Gly985Arg)

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.2953G>A (p.Gly985Arg)

Other names:

p.G985R:GGG>AGG

HGVS:

NC_000015.10:g.48489980C>T
NG_008805.2:g.160809G>A
NM_000138.5:c.2953G>AMANE SELECT
NP_000129.3:p.Gly985Arg
NP_000129.3:p.Gly985Arg
LRG_778t1:c.2953G>A
LRG_778:g.160809G>A
LRG_778p1:p.Gly985Arg
NC_000015.9:g.48782177C>T
NM_000138.4:c.2953G>A

Protein change:

G985R

Links:

dbSNP: rs794728199

NCBI 1000 Genomes Browser:

rs794728199

Molecular consequence:

NM_000138.5:c.2953G>A - 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
SCV000319440	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Mar 31, 2017)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10441597, 11700157, 16220557, 17627385, 19293843, 19863550, 27611364 Citation Link,
SCV004240570	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 8, 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

SCV000319440

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Mar 31, 2017)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link,

SCV004240570

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 8, 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

Demonstration of the recurrence of Marfan-like skeletal and cardiovascular manifestations due to germline mosaicism for an FBN1 mutation.

Collod-Béroud G, Lackmy-Port-Lys M, Jondeau G, Mathieu M, Maingourd Y, Coulon M, Guillotel M, Junien C, Boileau C.

Am J Hum Genet. 1999 Sep;65(3):917-21. No abstract available.

PubMed [citation]

PMID:: 10441597
PMCID:: PMC1377997

Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome.

Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A.

Arch Intern Med. 2001 Nov 12;161(20):2447-54.

PubMed [citation]

PMID:: 11700157

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000319440.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.G985R variant (also known as c.2953G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2953. The glycine at codon 985 is replaced by arginine, an amino acid with dissimilar properties, and is located in the TGFBP #03 domain. This alteration has been identified in multiple individuals with classical Marfan syndrome and reported to co-segregate with disease (Loeys B et al. Arc Intern Med. 2001;161(20):2447-54; Howarth R et al. Genet. Test., 2007;11:146-52; Ware AL et al. Cardiovasc. Pathol. 2016 Jun;25:418-22). Another study has suggested that this alteration does not co-segregate with disease (Yang H et al. Sci Rep, 2016 Sep;6:33002). An alteration affecting the same amino acid (p.G985E, c.2954G>A) has been reported in individuals with classical Marfan syndrome (Collod-Béroud G et al. Am. J. Hum. Genet., 1999 Sep;65:917-21; Stheneur C et al. Eur. J. Hum. Genet., 2009 Sep;17:1121-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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, SCV004240570.1

#	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 20, 2024

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