NM_000138.5(FBN1):c.7241G>A (p.Arg2414Gln) AND Marfan syndrome

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Dec 1, 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:: RCV000148488.9

Allele description [Variation Report for NM_000138.5(FBN1):c.7241G>A (p.Arg2414Gln)]

NM_000138.5(FBN1):c.7241G>A (p.Arg2414Gln)

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.7241G>A (p.Arg2414Gln)

HGVS:

NC_000015.10:g.48425828C>T
NG_008805.2:g.224961G>A
NM_000138.5:c.7241G>AMANE SELECT
NP_000129.3:p.Arg2414Gln
NP_000129.3:p.Arg2414Gln
LRG_778t1:c.7241G>A
LRG_778:g.224961G>A
LRG_778p1:p.Arg2414Gln
NC_000015.9:g.48718025C>T
NM_000138.4:c.7241G>A

Protein change:

R2414Q

Links:

dbSNP: rs143863014

NCBI 1000 Genomes Browser:

rs143863014

Molecular consequence:

NM_000138.5:c.7241G>A - 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
SCV000190192	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Likely benign (Jun 1, 2014)	germline	research
SCV000267312	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 18, 2016)	germline	reference population	PubMed (3) [See all records that cite these PMIDs] 16835936, 24941995, 25741868
SCV001275175	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24941995, 25812041, 16835936, 25637381 Citation Link,
SCV004822390	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 1, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16835936, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	12	not provided	not provided	108544	not provided	clinical testing, research
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome.

Yang RQ, Jabbari J, Cheng XS, Jabbari R, Nielsen JB, Risgaard B, Chen X, Sajadieh A, Haunsø S, Svendsen JH, Olesen MS, Tfelt-Hansen J.

BMC Genet. 2014 Jun 18;15:74. doi: 10.1186/1471-2156-15-74.

PubMed [citation]

PMID:: 24941995
PMCID:: PMC4070351

Difficulties in diagnosing Marfan syndrome using current FBN1 databases.

Groth KA, Gaustadnes M, Thorsen K, Østergaard JR, Jensen UB, Gravholt CH, Andersen NH.

Genet Med. 2016 Jan;18(1):98-102. doi: 10.1038/gim.2015.32. Epub 2015 Mar 26. Review.

PubMed [citation]

PMID:: 25812041

See all PubMed Citations (5)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190192.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267312.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (3)

#	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		1	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001275175.1

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

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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, SCV004822390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	12	not provided	not provided	clinical testing	PubMed (2)

Description

This missense variant replaces arginine with glutamine at codon 2414 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two related individuals with Marfan-related phenotype from a family with history of Marfan syndrome (PMID: 16835936). This variant has not been identified 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		12	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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