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NM_000138.5(FBN1):c.994C>T (p.Arg332Cys) AND Marfan syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 24, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV004004932.3

Allele description [Variation Report for NM_000138.5(FBN1):c.994C>T (p.Arg332Cys)]

NM_000138.5(FBN1):c.994C>T (p.Arg332Cys)

Genes:
LOC113939944:Sharpr-MPRA regulatory region 9539 [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.994C>T (p.Arg332Cys)
HGVS:
  • NC_000015.10:g.48520812G>A
  • NG_008805.2:g.129977C>T
  • NG_063729.1:g.381G>A
  • NM_000138.5:c.994C>TMANE SELECT
  • NP_000129.3:p.Arg332Cys
  • LRG_778t1:c.994C>T
  • LRG_778:g.129977C>T
  • NC_000015.9:g.48813009G>A
  • NM_000138.4:c.994C>T
  • p.Arg332Cys
Protein change:
R332C
Links:
dbSNP: rs1161109360
NCBI 1000 Genomes Browser:
rs1161109360
Molecular consequence:
  • NM_000138.5:c.994C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004823092All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)		Uncertain Significance
(May 16, 2023) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005049304Baylor Genetics
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 24, 2024) 		unknownclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided108544not providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

FBN1 mutations largely contribute to sporadic non-syndromic aortic dissection.

Tan L, Li Z, Zhou C, Cao Y, Zhang L, Li X, Cianflone K, Wang Y, Wang DW.

Hum Mol Genet. 2017 Dec 15;26(24):4814-4822. doi: 10.1093/hmg/ddx360.

PubMed [citation]
PMID:
28973303

Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm.

Li Y, Kong Y, Duan W, Yu S, Zhou X, Hu Y, Ou JS, Yi D, Xie J, Zhu J, Sun L, Li Y, Du J.

Eur J Hum Genet. 2021 Jul;29(7):1129-1138. doi: 10.1038/s41431-021-00857-2. Epub 2021 Apr 6.

PubMed [citation]
PMID:
33824467
PMCID:
PMC8298584
See all PubMed Citations (3)

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004823092.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

This missense variant replaces arginine with cysteine at codon 332 of the FBN1 protein. Computational prediction suggests that this variant may have 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 an individual affected with non-syndromic aortic dissection (PMID: 28973303) and in another individual affected with isolated thoracic aortic aneurysm and dissection (PMID: 33824467). This variant has been identified in 1/251234 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided1not providednot providednot provided

From Baylor Genetics, SCV005049304.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024