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NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter) AND Marfan syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Feb 22, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV000659558.2

Allele description [Variation Report for NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter)]

NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter)

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.5826C>A (p.Cys1942Ter)
Other names:
NM_000138.5(FBN1):c.5826C>A; p.Cys1942Ter
HGVS:
  • NC_000015.10:g.48445467G>T
  • NG_008805.2:g.205322C>A
  • NM_000138.5:c.5826C>AMANE SELECT
  • NP_000129.3:p.Cys1942Ter
  • NP_000129.3:p.Cys1942Ter
  • LRG_778t1:c.5826C>A
  • LRG_778:g.205322C>A
  • LRG_778p1:p.Cys1942Ter
  • NC_000015.9:g.48737664G>T
  • NM_000138.4:c.5826C>A
Protein change:
C1942*
Links:
dbSNP: rs363806
NCBI 1000 Genomes Browser:
rs363806
Molecular consequence:
  • NM_000138.5:c.5826C>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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000781391Center for Human Genetics, Inc, Center for Human Genetics, Inc
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Nov 1, 2016) 		germlineclinical testing

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

SCV004704623ClinGen FBN1 Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)		Pathogenic
(Feb 22, 2024) 		germlinecuration

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000781391.1

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

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004704623.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The NM_00138 c.5826C>A, is a nonsense variant in FBN1 expected to cause a premature stop codon and likely results in an absent or disrupted protein product (PVS1). This variant was found in a proband with infantile Marfan syndrome (MFS) and was found to be de novo without confirmation of parental relationships (internal data, PP4, PM6_Supporting). This variant has been reported 7 times in ClinVar, twice as pathogenic and five times as uncertain significance (Variantion ID: 547334). At least three other probands with clinical features of MFS carry the same variant (PMID 12068374, 22772377, Centre for Human Genetics ClinVar entry, PS4_Sup). In one family with features of MFS, including mitral valve prolapse, striae, pectus carinatum, scoliosis, striae, joint hypermobility, and wrist and thumb sign, this variant was found to segregate with disease in four affected family members (PMID 12068374, PP1). This variant is not present in gnomAD (PM2_sup; https://gnomad.broadinstitute.org/ v2.1.1). In summary, this variant meets criteria to be classified as pathogenic for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: PVS1, PS4_Sup, PM2_Sup, PM6_Sup, PP1, PP4

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

Last Updated: May 1, 2024