NM_000138.5:c.2927G>A

Variant names:

• chr15-48490006-C-T
• rs140954477
• NM_000138.5:c.2927G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM5 PP2 PP3 BP6

The NM_000138.5(FBN1):​c.2927G>A​(p.Arg976His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000109 in 1,614,126 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R976C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 7.90
• Publications: 17 publications found

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 19 uncertain in NM_000138.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-48490007-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 200006.
• PP2: Missense variant in the FBN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 1311 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.0644 (above the threshold of 3.09). Trascript score misZ: 8.1787 (above the threshold of 3.09). GenCC associations: The gene is linked to Marfan syndrome, Weill-Marchesani syndrome 2, dominant, progeroid and marfanoid aspect-lipodystrophy syndrome, geleophysic dysplasia, Shprintzen-Goldberg syndrome, stiff skin syndrome, familial thoracic aortic aneurysm and aortic dissection, isolated ectopia lentis, ectopia lentis 1, isolated, autosomal dominant, Acromicric dysplasia, neonatal Marfan syndrome, Weill-Marchesani syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• BP6: Variant 15-48490006-C-T is Benign according to our data. Variant chr15-48490006-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42321.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN1	NM_000138.5	c.2927G>A	p.Arg976His	missense_variant	Exon 25 of 66	ENST00000316623.10	NP_000129.3
FBN1	NM_001406716.1	c.2927G>A	p.Arg976His	missense_variant	Exon 24 of 65		NP_001393645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN1	ENST00000316623.10	c.2927G>A	p.Arg976His	missense_variant	Exon 25 of 66	1	NM_000138.5	ENSP00000325527.5

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152124 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 27 AN: 251460 AF XY: 0.000118

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727240

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000139 AC: 155 AN: 1112006

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152242 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74434

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000990 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:3

Nov 10, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R976H variant (also known as c.2927G>A), located in coding exon 24 of the FBN1 gene, results from a G to A substitution at nucleotide position 2927. The arginine at codon 976 is replaced by histidine, an amino acid with highly similar properties, and is located in the TGFBP#03 domain. This variant was reported in a patient described to have classic Marfan syndrome (MS) (Comeglio P et al. Hum Mutat. 2007;28(9):928) and in cohorts of individuals with symptoms of Marfan syndrome (Robinson DO et al. Clin Genet. 2012;82(3):223-31; Wooderchak-Donahue W et al. Am. J. Med. Genet. A. 2015;167A:1747-57; Vatti L et al. Am. J. Med. Genet. A. 2017:epub ahead of print); however, clinical details were limited in all studies. This variant has also been seen in exome cohorts not selected for presence of MFS or cardiovascular findings; however, clinical history was limited or not provided (Yang RQ et al. BMC Genet. 2014;15:74; Amendola LM et al. Genome Res. 2015;25(3):305-15; Retterer K et al. Genet Med. 2016 07;18(7):696-704; Damrauer SM et al. Circ Genom Precis Med. 2019 06;12(6):e002454). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -

Apr 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with histidine at codon 976 of the FBN1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. 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 one individual suspected to be affected with 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 elevated variant allele frequency in the general population indicates that this variant may not be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Marfan syndrome Uncertain:2 Benign:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Mar 27, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

not specified Uncertain:1

May 01, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

FBN1-related disorder Uncertain:1

Mar 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FBN1 c.2927G>A variant is predicted to result in the amino acid substitution p.Arg976His. This variant has been reported in multiple individuals with Marfan syndrome; however, clinical information was limited and family studies were not reported to help assess the variant's pathogenicity (Comeglio et al. 2007. PubMed ID: 17657824; Robinson et al. 2011. PubMed ID: 21895641; Wooderchak-Donahue et al. 2015. PubMed ID: 25944730; Groth et al. 2015. PubMed ID: 25812041). This variant has also been reported in individuals without Marfan syndrome (Damrauer et al. 2019. PubMed ID: 31211626) and, in one study, reported in an individual with features of Marfan syndrome who harbored an additional variant in FBN1 that was more likely to explain the phenotype (Table S6, Lerner-Ellis et al. 2014. PubMed ID: 24793577). This variant is reported in 0.015% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations in the ClinVar database, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/42321/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Connective tissue disorder Uncertain:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.68	D
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.86
Sift	Benign	0.059	T
Sift4G	Benign	0.17	T
Vest4		0.83
MVP		0.89
MPC		1.6
ClinPred		0.55	D
GERP RS		5.7
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs140954477; hg19: chr15-48782203; COSMIC: COSV57315422;