NM_000138.5(FBN1):c.8268G>A (p.Trp2756Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 13, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001851898.13

Allele description [Variation Report for NM_000138.5(FBN1):c.8268G>A (p.Trp2756Ter)]

NM_000138.5(FBN1):c.8268G>A (p.Trp2756Ter)

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.8268G>A (p.Trp2756Ter)

Other names:

FBN1, G8268A, TRP2756TER; W2756*

HGVS:

NC_000015.10:g.48411338C>T
NG_008805.2:g.239451G>A
NM_000138.5:c.8268G>AMANE SELECT
NP_000129.3:p.Trp2756Ter
NP_000129.3:p.Trp2756Ter
LRG_778t1:c.8268G>A
LRG_778:g.239451G>A
LRG_778p1:p.Trp2756Ter
NC_000015.9:g.48703535C>T
NM_000138.4:c.8268G>A

Protein change:

TRP2756TER

Links:

OMIM: 134797.0004; dbSNP: rs267606796

NCBI 1000 Genomes Browser:

rs267606796

Molecular consequence:

NM_000138.5:c.8268G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Marfan syndrome (MFS)
Synonyms:: MARFAN SYNDROME, TYPE I; Marfan syndrome type 1; Marfan's syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007947; MedGen: C0024796; Orphanet: 284963; Orphanet: 558; OMIM: 154700

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
SCV002236718	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 13, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1631074, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002236718

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 13, 2023)

germline

clinical testing

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

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

Two mutations in Marfan syndrome resulting in truncated fibrillin polypeptides.

Kainulainen K, Sakai LY, Child A, Pope FM, Puhakka L, Ryhänen L, Palotie A, Kaitila I, Peltonen L.

Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5917-21.

PubMed [citation]

PMID:: 1631074
PMCID:: PMC49408

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002236718.3

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

Description

This sequence change creates a premature translational stop signal (p.Trp2756*) in the FBN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 116 amino acid(s) of the FBN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Marfan syndrome (PMID: 1631074). This variant is also known as a G-to-A transition at nucleotide 5574. ClinVar contains an entry for this variant (Variation ID: 16424). This variant disrupts a region of the FBN1 protein in which other variant(s) (p.Leu2854Profs*9) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as 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

Last Updated: Jun 2, 2024

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