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NM_000138.4(FBN1):c.1585C>T (p.Arg529Ter) AND not provided

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Jul 28, 2017
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:
RCV000181685.3

Allele description

NM_000138.4(FBN1):c.1585C>T (p.Arg529Ter)

Gene:
FBN1:fibrillin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q21.1
Genomic location:
Preferred name:
NM_000138.4(FBN1):c.1585C>T (p.Arg529Ter)
Other names:
p.R529X:CGA>TGA
HGVS:
  • NC_000015.10:g.48513552G>A
  • NG_008805.2:g.137237C>T
  • NM_000138.4:c.1585C>T
  • NP_000129.3:p.Arg529Ter
  • LRG_778t1:c.1585C>T
  • LRG_778:g.137237C>T
  • LRG_778p1:p.Arg529Ter
  • NC_000015.9:g.48805749G>A
  • p.Arg529*
Protein change:
R529*; ARG529TER
Links:
OMIM: 134797.0033; dbSNP: rs137854476
NCBI 1000 Genomes Browser:
rs137854476
Molecular consequence:
  • NM_000138.4:c.1585C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000233988GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Pathogenic
(Dec 29, 2016) 		germlineclinical testing

Citation Link,

SCV000885417ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Pathogenic
(Jul 28, 2017) 		germlineclinical testing

Citation Link

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Summary from all submissions

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

Details of each submission

From GeneDx, SCV000233988.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The R529X variant in the FBN1 gene has been previously reported in association with Marfan syndrome (Rand-Hendrickson et al., 2007; Montgomery et al., 1999; Das et al., 2012; Tjeldhorn et al., 2006; Sšylen et al., 2009; Hung et al., 2009; Ogawa et al., 2011; Stheneur et al., 2009). Rand- Hendrickson et al. (2007) reported on two Norwegian index patients with the R529X variant and classical characteristics of Marfan syndrome. Tjeldhorn et al. (2006) reported on one patient with Marfan syndrome and the R529X variant, which was absent from 46 control chromosomes. Additionally, one individual with R529X variant that met the Ghent criteria was reported in a study of 294 Taiwanese patients, and was not present in 50 unaffected ethnically - matched controls (Hung et al., 2009). Furthermore, R529X variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations A Japanese study of 53 patients with suspected Marfan syndrome identified 1 patient with the R529X variant (Ogawa et al., 2011). Finally, Stheneur et al. (2009), screened 586 French patients with a clinical diagnosis of Marfan syndrome and identified one individual with the R529X variant. Montgomery et al. (1999) reported a 7% level of mutant transcript and near absence of immunohistochemical staining of fibrillin-1 in cultured fibroblasts for an individual with an inherited R529X variant who had aortic abnormalities and skeletal manifestations. This reduction in the mutant allele was attributed to the R529X causing nonsense-mediated mRNA decay (Montgomery et al., 1999). Lastly, other nonsense variant in the FBN1 gene have been reported in association with Marfan syndrome. In summary, R529X in the FBN1 gene is interpreted as a disease-causing variant.

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

From ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories, SCV000885417.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The FBN1 c.1585C>T; p.Arg529Ter variant (rs137854476) has been reported multiple times in the literature in individuals with Marfan syndrome (Hung 2009, Montgomery 1998, Rand-Hendriksen 2007, Soylen 2009, Stheneur 2009, Tjeldhorn 2006). It is reported as pathogenic in the ClinVar database (Variation ID: 16452), and is absent from general population databases (1000 Genome Project, Exome Variant Server, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Arg529Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/16452/ Hung CC et al. Mutation spectrum of the fibrillin-1 (FBN1) gene in Taiwanese patients with Marfan syndrome. Ann Hum Genet. 2009 Nov;73(Pt 6):559-67. Montgomery RA et al. Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome. Am J Hum Genet. 1998 Dec;63(6):1703-11. Rand-Hendriksen S et al. Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan syndrome. Am J Med Genet A. 2007 Sep 1;143A(17):1968-77. Soylen B et al. Prevalence of dural ectasia in 63 gene-mutation-positive patients with features of Marfan syndrome type 1 and Loeys-Dietz syndrome and report of 22 novel FBN1 mutations. Clin Genet. 2009 Mar;75(3):265-70. Stheneur C et al. Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. Eur J Hum Genet. 2009 Sep;17(9):1121-8. Tjeldhorn L et al. Rapid and efficient FBN1 mutation detection using automated sample preparation and direct sequencing as the primary strategy. Genet Test. 2006 Winter;10(4):258-64.

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

Last Updated: Mar 31, 2019