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NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 28, 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:
RCV000808826.8

Allele description [Variation Report for NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn)]

NM_000138.5(FBN1):c.3712G>A (p.Asp1238Asn)

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.3712G>A (p.Asp1238Asn)
Other names:
p.D1238N:GAC>AAC; NM_000138.5(FBN1):c.3712G>A; p.Asp1238Asn
HGVS:
  • NC_000015.10:g.48485374C>T
  • NG_008805.2:g.165415G>A
  • NM_000138.5:c.3712G>AMANE SELECT
  • NP_000129.3:p.Asp1238Asn
  • NP_000129.3:p.Asp1238Asn
  • LRG_778t1:c.3712G>A
  • LRG_778:g.165415G>A
  • LRG_778p1:p.Asp1238Asn
  • NC_000015.9:g.48777571C>T
  • NM_000138.4:c.3712G>A
Protein change:
D1238N
Links:
dbSNP: rs794728208
NCBI 1000 Genomes Browser:
rs794728208
Molecular consequence:
  • NM_000138.5:c.3712G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000948948Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Dec 28, 2023) 		germlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Comparison of heteroduplex analysis, direct sequencing, and enzyme mismatch cleavage for detecting mutations in a large gene, FBN1.

Yuan B, Thomas JP, von Kodolitsch Y, Pyeritz RE.

Hum Mutat. 1999;14(5):440-6.

PubMed [citation]
PMID:
10533071

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]
PMID:
17576681
PMCID:
PMC1934990
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000948948.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1238 of the FBN1 protein (p.Asp1238Asn). This variant also falls at the last nucleotide of exon 30, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Marfan syndrome (PMID: 10533071; Invitae). ClinVar contains an entry for this variant (Variation ID: 200022). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024