NM_000138.5(FBN1):c.2927G>A (p.Arg976His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 9, 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:: RCV000588311.22

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000233773	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 9, 2024)	germline	clinical testing	Citation Link,
SCV000695498	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Mar 27, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24941995, 25812041, 27647783, 24793577, 25944730, 17657824, 25839328, 25637381, 21895641 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001474399	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Uncertain significance (Sep 21, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000233773

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 9, 2024)

germline

clinical testing

Citation Link,

SCV000695498

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Mar 27, 2017)

germline

clinical testing

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

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV001474399

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)

Uncertain significance
(Sep 21, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

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 (9)

Details of each submission

From GeneDx, SCV000233773.10

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

Description

Reported in association with Marfan syndrome; however, at least one patient harbored a second FBN1 variant (p. C534Y) which was suspected to be the cause of disease (PMID: 17657824, 25944730, 28941062, 24793577); Although located in a TGF-binding protein domain (aka TB domain or 8-Cysteine domain), it does not affect a cysteine residue within this domain; other missense substitutions that affect cysteine residues within this TGF-binding protein domain have been reported in association with various FBN1-related phenotypes (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28941062, 25637381, 25812041, 27647783, 24941995, 21895641, 25944730, 31211626, 24793577, 26633542, 25839328, 35130036, 34663891, 17657824, 32123317)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695498.1

#	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.2927G>A (p.Arg976His) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within a TB domain (InterPro) and 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing, but ESE finder predicts that this variant may affect several ESE sites at the locus. However, a functional study determined that the variant had no effect on splicing via RNA analysis in patient blood samples (Robinson_ClinGen_2012). This variant was found in the large control database ExAC at a frequency of 0.00014 (17/121462 control chromosomes), which is slightly above estimated maximal expected allele frequency of a pathogenic FBN1 variant (0.0001125), suggesting this variant is likely a benign polymorphism. The variant was also detected in a patient cohort co-occurring with a likely pathogenic variant (Lerner-Ellis_MGM_2014; p.Cys534Tyr), further supporting the benign nature of the variant of interest. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as one of uncertain significance; however, 2 of the entries were reported prior to the release of the ExAC database, and 1 entry (from 2016) cites only the ESP database as a source for control population data (GeneDx; see description provided below in the ClinVar additional comments). Taken together, this variant is classified as likely benign.

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001474399.3

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

Description

The FBN1 c.2927G>A; p.Arg976His variant (rs140954477) is reported in the literature in individuals with symptoms of Marfan syndrome (Comeglio 2007, Robinson 2012), but is also reported in Marfan syndrome patient who also carried a likely pathogenic FBN1 variant (Lerner-Ellis 2014). This variant is reported in ClinVar (Variation ID: 42321), and is found in the general population with an overall allele frequency of 0.01% (29/282840 alleles) in the Genome Aggregation Database. The arginine at codon 976 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.862). While the population frequency (Yang 2014) and presence in a patient with a different disease-causing variant (Lerner-Ellis 2014) suggest that this variant does not cause disease, given the minimal clinical and functional data, the significance of the p.Arg976His variant is uncertain at this time. References: Comeglio P et al. The importance of mutation detection in Marfan syndrome and Marfan-related disorders: report of 193 FBN1 mutations. Hum Mutat. 2007 Sep;28(9):928. Lerner-Ellis JP et al. The spectrum of FBN1, TGFßR1, TGFßR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD). Mol Genet Metab. 2014 Jun;112(2):171-6. Robinson DO et al. Systematic screening of FBN1 gene unclassified missense variants for splice abnormalities. Clin Genet. 2012 Sep;82(3):223-31. Yang RQ et al. New population-based exome data question the pathogenicity of some genetic variants previously associated with Marfan syndrome. BMC Genet. 2014 Jun 18;15:74.

#	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 13, 2024

ClinVar

Relating variation to medicine