NM_000138.5(FBN1):c.8363C>T (p.Thr2788Met) AND Marfan syndrome

Germline classification:: Benign (3 submissions)
Last evaluated:: Feb 1, 2023
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:: RCV000279195.15

Allele description [Variation Report for NM_000138.5(FBN1):c.8363C>T (p.Thr2788Met)]

NM_000138.5(FBN1):c.8363C>T (p.Thr2788Met)

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.8363C>T (p.Thr2788Met)

Other names:

NM_000138.4(FBN1):c.8363C>T; p.Thr2788Met

HGVS:

NC_000015.10:g.48411243G>A
NG_008805.2:g.239546C>T
NM_000138.5:c.8363C>TMANE SELECT
NP_000129.3:p.Thr2788Met
NP_000129.3:p.Thr2788Met
LRG_778t1:c.8363C>T
LRG_778:g.239546C>T
LRG_778p1:p.Thr2788Met
NC_000015.9:g.48703440G>A
NM_000138.4:c.8363C>T

Protein change:

T2788M

Links:

dbSNP: rs143007898

NCBI 1000 Genomes Browser:

rs143007898

Molecular consequence:

NM_000138.5:c.8363C>T - missense variant - [Sequence Ontology: SO:0001583]

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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Rhaphiolepis umbellata voucher hachi048 trnH-psbA intergenic spacer, partial seq...
Rhaphiolepis umbellata voucher hachi048 trnH-psbA intergenic spacer, partial sequence; chloroplast
gi|2314651085|gnl|uoguelph|JWP4925- nH-psbA|gb|OK418599.1|

Nucleotide
ankyrin repeat domain-containing protein SOWAHD [Mus musculus]
ankyrin repeat domain-containing protein SOWAHD [Mus musculus]
gi|30424651|ref|NP_776140.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000392039	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Likely benign (Jun 14, 2016)	germline	clinical testing	ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000787410	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Likely benign (Nov 7, 2017)	germline	clinical testing
SCV003762195	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Benign (Feb 1, 2023)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000392039

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Likely benign
(Jun 14, 2016)

germline

clinical testing

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV000787410

Center for Medical Genetics Ghent, University of Ghent

no assertion criteria provided

Likely benign
(Nov 7, 2017)

germline

clinical testing

SCV003762195

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)

Benign
(Feb 1, 2023)

germline

curation

Citation Link

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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, curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000392039.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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

From Center for Medical Genetics Ghent, University of Ghent, SCV000787410.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV003762195.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_00138 c.8363C>T, is a missense variant in FBN1 predicted to cause a substitution of a threonine by methionine at amino acid 2788 (p.Thr2788Met). The variant in FBN1 has been reported 13 times in ClinVar: 12 times as likely benign and once as benign (Variation ID: 263832). This variant has been identified in 44 individuals of African origin (gnomAD version 3.1.1, MAF: 0.1%, one homozygous) (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear on the predicted impact on the protein (REVEL: 0.356). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1.

#	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: Oct 26, 2024

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