NM_000138.5(FBN1):c.2927G>A (p.Arg976His) AND Marfan syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Mar 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000148497.14

Allele description [Variation Report for NM_000138.5(FBN1):c.2927G>A (p.Arg976His)]

NM_000138.5(FBN1):c.2927G>A (p.Arg976His)

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.2927G>A (p.Arg976His)

Other names:

p.R976H:CGC>CAC

HGVS:

NC_000015.10:g.48490006C>T
NG_008805.2:g.160783G>A
NM_000138.5:c.2927G>AMANE SELECT
NP_000129.3:p.Arg976His
NP_000129.3:p.Arg976His
LRG_778t1:c.2927G>A
LRG_778:g.160783G>A
LRG_778p1:p.Arg976His
NC_000015.9:g.48782203C>T
NM_000138.4:c.2927G>A
c.2927G>A

Protein change:

R976H

Links:

dbSNP: rs140954477

NCBI 1000 Genomes Browser:

rs140954477

Molecular consequence:

NM_000138.5:c.2927G>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

Recent activity

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hypothetical protein GCK72_024643 [Caenorhabditis remanei]
hypothetical protein GCK72_024643 [Caenorhabditis remanei]
gi|2445394432|ref|XP_053579540.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190206	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Uncertain significance (Jun 1, 2014)	germline	research
SCV004808033	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814853	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17657824, 21895641, 24793577, 25944730, 28941062, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190206

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Uncertain significance
(Jun 1, 2014)

germline

research

SCV004808033

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Mar 29, 2024)

germline

clinical testing

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

SCV004814853

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

PubMed (6)
[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	25	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations.

Comeglio P, Johnson P, Arno G, Brice G, Evans A, Aragon-Martin J, da Silva FP, Kiotsekoglou A, Child A.

Hum Mutat. 2007 Sep;28(9):928.

PubMed [citation]

PMID:: 17657824

Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities.

Robinson DO, Lin F, Lyon M, Raponi M, Cross E, White HE, Cox H, Clayton-Smith J, Baralle D.

Clin Genet. 2012 Sep;82(3):223-31. doi: 10.1111/j.1399-0004.2011.01781.x. Epub 2011 Sep 30.

PubMed [citation]

PMID:: 21895641

See all PubMed Citations (6)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190206.1

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004808033.1

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

#	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, SCV004814853.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	25	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces arginine with histidine at codon 976 of the FBN1 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Marfan syndrome (PMID: 17657824, 21895641, 25944730, 28941062). It has also been reported in an individual affected with clinical features of Marfan syndrome who also carried a different pathogenic missense variant in the same gene (PMID: 24793577). This variant has been identified in 29/282840 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		25	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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