NM_000138.5(FBN1):c.2927G>A (p.Arg976His) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 3, 2024
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:: RCV000777744.18

Allele description [Variation Report for NM_000138.5(FBN1):c.2927G>A (p.Arg976His)]

NM_000138.5(FBN1):c.2927G>A (p.Arg976His)

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.2927G>A (p.Arg976His)

Other names:

p.R976H:CGC>CAC

HGVS:

NC_000015.10:g.48490006C>T
NG_008805.2:g.160783G>A
NM_000138.5:c.2927G>AMANE SELECT
NP_000129.3:p.Arg976His
NP_000129.3:p.Arg976His
LRG_778t1:c.2927G>A
LRG_778:g.160783G>A
LRG_778p1:p.Arg976His
NC_000015.9:g.48782203C>T
NM_000138.4:c.2927G>A
c.2927G>A

Protein change:

R976H

Links:

dbSNP: rs140954477

NCBI 1000 Genomes Browser:

rs140954477

Molecular consequence:

NM_000138.5:c.2927G>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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hypothetical protein GCK72_024643 [Caenorhabditis remanei]
hypothetical protein GCK72_024643 [Caenorhabditis remanei]
gi|2445394432|ref|XP_053579540.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000913705	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 20, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17657824, 21895641, 24793577, 25944730, 28941062, 25741868
SCV002041966	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002748536	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jan 3, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25944730, 26633542, 28941062, 31211626 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000913705

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 20, 2023)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002041966

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 10, 2021)

germline

clinical testing

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

SCV002748536

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jan 3, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

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

The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.

Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, da Silva FP, Kiotsekoglou A, Child A.

Hum Mutat. 2007 Sep;28(9):928.

PubMed [citation]

PMID:: 17657824

Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities.

Robinson DO, Lin F, Lyon M, Raponi M, Cross E, White HE, Cox H, Clayton-Smith J, Baralle D.

Clin Genet. 2012 Sep;82(3):223-31. doi: 10.1111/j.1399-0004.2011.01781.x. Epub 2011 Sep 30.

PubMed [citation]

PMID:: 21895641

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000913705.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces arginine with histidine at codon 976 of the FBN1 protein. Computational prediction suggests that this variant may have a 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 individuals affected with Marfan syndrome (PMID: 17657824, 21895641, 25944730, 28941062). It has also been reported in an individual affected with clinical features of Marfan syndrome who also carried a different pathogenic missense variant in the same gene (PMID: 24793577). This variant has been identified in 29/282840 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, SCV002041966.2

#	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

From Ambry Genetics, SCV002748536.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.R976H variant (also known as c.2927G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2927. The arginine at codon 976 is replaced by histidine, an amino acid with highly similar properties, and is located in the TGFBP#03 domain. This variant was reported in a patient described to have classic Marfan syndrome (MS) (Comeglio P et al. Hum Mutat. 2007;28(9):928) and in cohorts of individuals with symptoms of Marfan syndrome (Robinson DO et al. Clin Genet. 2012;82(3):223-31; Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57; Vatti L et al. Am. J. Med. Genet. A. 2017:epub ahead of print); however, clinical details were limited in all studies. This variant has also been seen in exome cohorts not selected for presence of MFS or cardiovascular findings; however, clinical history was limited or not provided (Yang RQ et al. BMC Genet. 2014;15:74; Amendola LM et al. Genome Res. 2015;25(3):305-15; Retterer K et al. Genet Med. 2016 07;18(7):696-704; Damrauer SM et al. Circ Genom Precis Med. 2019 06;12(6):e002454). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting 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: Oct 13, 2024

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