NM_000138.5(FBN1):c.2237A>G (p.Tyr746Cys) AND Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 8, 2017
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:: RCV000590010.1

Allele description [Variation Report for NM_000138.5(FBN1):c.2237A>G (p.Tyr746Cys)]

NM_000138.5(FBN1):c.2237A>G (p.Tyr746Cys)

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.2237A>G (p.Tyr746Cys)

HGVS:

NC_000015.10:g.48497322T>C
NG_008805.2:g.153467A>G
NM_000138.5:c.2237A>GMANE SELECT
NP_000129.3:p.Tyr746Cys
NP_000129.3:p.Tyr746Cys
LRG_778t1:c.2237A>G
LRG_778:g.153467A>G
LRG_778p1:p.Tyr746Cys
NC_000015.9:g.48789519T>C
NM_000138.4:c.2237A>G

Protein change:

Y746C

Links:

dbSNP: rs1555399372

NCBI 1000 Genomes Browser:

rs1555399372

Molecular consequence:

NM_000138.5:c.2237A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Marfan Syndrome/Loeys-Dietz Syndrome/Familial Thoracic Aortic Aneurysms and Dissections
Identifiers:: MedGen: CN229799

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000695482	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 8, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 11068200, 11880731, 8791520, 11143906, 8541880, 7611299, 10942427, 9401003, 9399842 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000695482

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Feb 8, 2017)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fibrillin: from domain structure to supramolecular assembly.

Handford PA, Downing AK, Reinhardt DP, Sakai LY.

Matrix Biol. 2000 Nov;19(6):457-70. Review.

PubMed [citation]

PMID:: 11068200

Marfan syndrome: orthopedic and genetic review.

Giampietro PF, Raggio C, Davis JG.

Curr Opin Pediatr. 2002 Feb;14(1):35-41. Review. Erratum in: Curr Opin Pediatr 2002 Apr;14(2):286.

PubMed [citation]

PMID:: 11880731

See all PubMed Citations (9)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695482.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: The FBN1 c.2237A>G (p.Tyr746Cys) variant involves the alteration of a conserved nucleotide and results in a replacement of a large size and aromatic Tyrosine (Y) with a medium size and polar Cysteine (C) located in a Ca-binding EGF-like domain (Giampietro_COP_2002). 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in the ExAC database (0/121350 control chromosomes), a large control database. A patient harboring the variant displayed a classic Marfan syndrome phenotype that involved "the ocular, skeletal, and cardiovascular systems" (Nijbroek_AJHG_1995). Family studies showed that the variant was a sporadic, de novo mutational event. Taken together and given that a cysteine is gained which is a frequent mechanism of disease, this variant is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jan 13, 2025

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