NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 5, 2024
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:: RCV000462664.10

Allele description [Variation Report for NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)]

NM_000138.5(FBN1):c.4621C>T (p.Arg1541Ter)

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.4621C>T (p.Arg1541Ter)

Other names:

p.R1541X:CGA>TGA

HGVS:

NC_000015.10:g.48468064G>A
NG_008805.2:g.182725C>T
NM_000138.5:c.4621C>TMANE SELECT
NP_000129.3:p.Arg1541Ter
NP_000129.3:p.Arg1541Ter
LRG_778t1:c.4621C>T
LRG_778:g.182725C>T
LRG_778p1:p.Arg1541Ter
NC_000015.9:g.48760261G>A
NM_000138.4:c.4621C>T

Protein change:

R1541*

Links:

dbSNP: rs794728228

NCBI 1000 Genomes Browser:

rs794728228

Molecular consequence:

NM_000138.5:c.4621C>T - 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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breast cancer type 1 susceptibility protein isoform 57 [Homo sapiens]
breast cancer type 1 susceptibility protein isoform 57 [Homo sapiens]
gi|2250232557|ref|NP_001394849.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544836	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 19293843, 10647894, 11933199, 12161601, 12700307, 16222657, 17657824, 23684891, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544836

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (9)
[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

Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene.

Stheneur C, Collod-Béroud G, Faivre L, Buyck JF, Gouya L, Le Parc JM, Moura B, Muti C, Grandchamp B, Sultan G, Claustres M, Aegerter P, Chevallier B, Jondeau G, Boileau C.

Eur J Hum Genet. 2009 Sep;17(9):1121-8. doi: 10.1038/ejhg.2009.36. Epub 2009 Mar 18.

PubMed [citation]

PMID:: 19293843
PMCID:: PMC2986588

Molecular analysis of eight mutations in FBN1.

Halliday D, Hutchinson S, Kettle S, Firth H, Wordsworth P, Handford PA.

Hum Genet. 1999 Dec;105(6):587-97.

PubMed [citation]

PMID:: 10647894

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544836.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change creates a premature translational stop signal (p.Arg1541*) in the FBN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FBN1 are known to be pathogenic (PMID: 17657824, 19293843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Marfan syndrome (PMID: 10647894, 11933199, 12161601, 12700307, 16222657, 17657824, 23684891). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 200052). 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: Sep 29, 2024

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