NM_000138.5(FBN1):c.5443G>A (p.Gly1815Ser) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jun 28, 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:: RCV001176350.6

Allele description [Variation Report for NM_000138.5(FBN1):c.5443G>A (p.Gly1815Ser)]

NM_000138.5(FBN1):c.5443G>A (p.Gly1815Ser)

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.5443G>A (p.Gly1815Ser)

Other names:

p.G1815S:GGC>AGC; NM_000138.5(FBN1):c.5443G>A; p.Gly1815Ser

HGVS:

NC_000015.10:g.48452664C>T
NG_008805.2:g.198125G>A
NM_000138.5:c.5443G>AMANE SELECT
NP_000129.3:p.Gly1815Ser
NP_000129.3:p.Gly1815Ser
LRG_778t1:c.5443G>A
LRG_778:g.198125G>A
LRG_778p1:p.Gly1815Ser
NC_000015.9:g.48744861C>T
NM_000138.4:c.5443G>A

Protein change:

G1815S

Links:

dbSNP: rs745680336

NCBI 1000 Genomes Browser:

rs745680336

Molecular consequence:

NM_000138.5:c.5443G>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
SCV001340314	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 28, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32655337, 25741868
SCV002653000	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27930701, 31227806, 32655337 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001340314

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 28, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002653000

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jun 2, 2022)

germline

clinical testing

PubMed (3)
[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

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

Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation.

Sanchez O, Campuzano O, Fernández-Falgueras A, Sarquella-Brugada G, Cesar S, Mademont I, Mates J, Pérez-Serra A, Coll M, Pico F, Iglesias A, Tirón C, Allegue C, Carro E, Gallego MÁ, Ferrer-Costa C, Hospital A, Bardalet N, Borondo JC, Vingut A, Arbelo E, Brugada J, et al.

PLoS One. 2016;11(12):e0167358. doi: 10.1371/journal.pone.0167358. Erratum in: PLoS One. 2017 Feb 6;12(2):e0171893. doi: 10.1371/journal.pone.0171893.

PubMed [citation]

PMID:: 27930701
PMCID:: PMC5145162

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001340314.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces glycine with serine at codon 1815 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual showing clinical features resembling Marfan syndrome (Cortini et al., 2020, DOI: 10.4103/ds.ds_16_19). This variant has been observed in homozygosity in two siblings affected with autism spectrum disorder, arachnodactyly and facial features consistent with Marfan syndrome but not affected with cardiovascular problems (PMID: 32655337). This variant has been identified in 4/251202 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, SCV002653000.2

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

Description

The p.G1815S variant (also known as c.5443G>A), located in coding exon 44 of the FBN1 gene, results from a G to A substitution at nucleotide position 5443. The glycine at codon 1815 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort and in an individual who had some overlapping features with Marfan syndrome (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358; Cortini F, et al. Dermatol Sin, 2020;38:98-101). This variant was also described as a homozygote in two siblings with autism, arachnodactyly and skeletal problems from a consanguineous mating. The parents were reported to be heterozygous for this alteration and absent of features of Marfan syndrome (Farajzadeh Valilou S et al. Mol Syndromol, 2020 Jun;11:62-72). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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: Sep 29, 2024

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