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NM_000138.5(FBN1):c.4460-8G>A AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 11, 2021
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:
RCV000768217.2

Allele description

NM_000138.5(FBN1):c.4460-8G>A

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.4460-8G>A
HGVS:
  • NC_000015.10:g.48468542C>T
  • NG_008805.2:g.182247G>A
  • NM_000138.5:c.4460-8G>AMANE SELECT
  • LRG_778t1:c.4460-8G>A
  • LRG_778:g.182247G>A
  • NC_000015.9:g.48760739C>T
  • NM_000138.4:c.4460-8G>A
Links:
dbSNP: rs193922204
NCBI 1000 Genomes Browser:
rs193922204
Molecular consequence:
  • NM_000138.5:c.4460-8G>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:
Ectopia lentis 1, isolated, autosomal dominant (ECTOL1)
Identifiers:
MONDO: MONDO:0007514; MedGen: C3541518; Orphanet: 1885; OMIM: 129600
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:
MASS syndrome (OCTD)
Synonyms:
Overlap connective tissue disease
Identifiers:
MONDO: MONDO:0011431; MedGen: C1858556; OMIM: 604308
Name:
Stiff skin syndrome (SSKS)
Identifiers:
MONDO: MONDO:0008492; MedGen: C1861456; OMIM: 184900
Name:
Weill-Marchesani syndrome 2, dominant
Synonyms:
Weill-Marchesani Syndrome, Autosomal Dominant; Weill-Marchesani syndrome 2; Glaucoma, Ectopia, Microspherophakia, Stiff joints and Short stature syndrome
Identifiers:
MONDO: MONDO:0012013; MedGen: C1869115; OMIM: 608328
Name:
Acromicric dysplasia (ACMICD)
Synonyms:
Acromicric skeletal dysplasia
Identifiers:
MONDO: MONDO:0007055; MedGen: C0265287; Orphanet: 969; OMIM: 102370
Name:
Geleophysic dysplasia 2 (GPHYSD2)
Identifiers:
MONDO: MONDO:0013612; MedGen: C3280054; Orphanet: 2623; OMIM: 614185
Name:
Progeroid and marfanoid aspect-lipodystrophy syndrome
Synonyms:
MARFANOID-PROGEROID SYNDROME; MARFAN-PROGEROID-LIPODYSTROPHY SYNDROME; Marfan lipodystrophy syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0014831; MedGen: C4310796; Orphanet: 300382; OMIM: 616914

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000898693Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Nov 11, 2021) 		germlineclinical testing

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

Help

Summary from all submissions

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

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 Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV000898693.2

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

Description

FBN1 NM_000138 exon 37 c.4460-8G>A: This variant has been reported in the literature in at least 3 individuals with features or a clinical suspicion of Marfan syndrome, segregating with disease in 2 affected family members (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243, Stheneur 2009 PMID:19293843). This variant is present in 1/33572 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs193922204). This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:36075). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is an intronic variant with no predicted change in the amino acid sequence but may have an unknown effect on splicing. Additional studies suggest that this variant may activate a cryptic acceptor site and impact the protein (Loeys 2001 PMID:11700157, Pepe 2007 PMID:18087243). However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.

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

Last Updated: Aug 25, 2024