NM_000138.5(FBN1):c.6890C>T (p.Thr2297Met) AND Marfan syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 13, 2023
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:: RCV000851302.7

Allele description [Variation Report for NM_000138.5(FBN1):c.6890C>T (p.Thr2297Met)]

NM_000138.5(FBN1):c.6890C>T (p.Thr2297Met)

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.6890C>T (p.Thr2297Met)

HGVS:

NC_000015.10:g.48428453G>A
NG_008805.2:g.222336C>T
NM_000138.5:c.6890C>TMANE SELECT
NP_000129.3:p.Thr2297Met
NP_000129.3:p.Thr2297Met
LRG_778t1:c.6890C>T
LRG_778:g.222336C>T
LRG_778p1:p.Thr2297Met
NC_000015.9:g.48720650G>A
NM_000138.4:c.6890C>T

Protein change:

T2297M

Links:

dbSNP: rs773785908

NCBI 1000 Genomes Browser:

rs773785908

Molecular consequence:

NM_000138.5:c.6890C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000993592	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - HudsonAlpha-AGHI-WGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 30, 2018)	paternal	research	PubMed (1) [See all records that cite this PMID]
SCV001275271	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	Citation Link,
SCV004822418	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27112580, 28550590, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000993592

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - HudsonAlpha-AGHI-WGS

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Aug 30, 2018)

paternal

research

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

SCV001275271

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Apr 27, 2017)

germline

clinical testing

Citation Link,

SCV004822418

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 13, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing
not provided	paternal	unknown	1	not provided	not provided	1	not provided	research

Citations

PubMed

Analysis of TGFBR1*6A variant in individuals evaluated for Marfan syndrome.

Somers AE, Hinton RB, Pilipenko V, Miller E, Ware SM.

Am J Med Genet A. 2016 Jul;170(7):1786-90. doi: 10.1002/ajmg.a.37668. Epub 2016 Apr 26.

PubMed [citation]

PMID:: 27112580

Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity.

Landis BJ, Schubert JA, Lai D, Jegga AG, Shikany AR, Foroud T, Ware SM, Hinton RB.

J Cardiovasc Transl Res. 2017 Aug;10(4):423-432. doi: 10.1007/s12265-017-9753-1. Epub 2017 May 26.

PubMed [citation]

PMID:: 28550590
PMCID:: PMC5702585

See all PubMed Citations (3)

Details of each submission

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - HudsonAlpha-AGHI-WGS, SCV000993592.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

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

From Illumina Laboratory Services, Illumina, SCV001275271.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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 All of Us Research Program, National Institutes of Health, SCV004822418.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces threonine with methionine at codon 2297 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 27112580, 28550590). This variant has been identified in 8/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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