NM_000138.5(FBN1):c.2956G>A (p.Ala986Thr) AND Marfan syndrome

Germline classification:: Benign (7 submissions)
Last evaluated:: Sep 26, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000029720.17

Allele description [Variation Report for NM_000138.5(FBN1):c.2956G>A (p.Ala986Thr)]

NM_000138.5(FBN1):c.2956G>A (p.Ala986Thr)

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.2956G>A (p.Ala986Thr)

Other names:

p.A986T:GCA>ACA; NM_000138.5(FBN1):c.2956G>A

HGVS:

NC_000015.10:g.48489977C>T
NG_008805.2:g.160812G>A
NM_000138.5:c.2956G>AMANE SELECT
NP_000129.3:p.Ala986Thr
NP_000129.3:p.Ala986Thr
LRG_778t1:c.2956G>A
LRG_778:g.160812G>A
LRG_778p1:p.Ala986Thr
NC_000015.9:g.48782174C>T
NM_000138.4:c.2956G>A
c.2956G>A

Protein change:

A986T

Links:

dbSNP: rs112287730

NCBI 1000 Genomes Browser:

rs112287730

Molecular consequence:

NM_000138.5:c.2956G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000052373	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	no assertion criteria provided	Benign (Mar 13, 2012)	germline	clinical testing
SCV000212201	CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Likely benign (Mar 11, 2015)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000257633	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Benign (Jul 9, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV000392514	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV000786906	Center for Medical Genetics Ghent, University of Ghent	no assertion criteria provided	Uncertain significance (Nov 7, 2017)	germline	clinical testing
SCV001139616	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV004037325	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Benign (Sep 26, 2023)	germline	curation	Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052373.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation, SCV000212201.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000257633.2

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

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

From Illumina Laboratory Services, Illumina, SCV000392514.3

#	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as 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 Center for Medical Genetics Ghent, University of Ghent, SCV000786906.1

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

#	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 Mendelics, SCV001139616.1

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

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

From ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004037325.1

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

Description

NM_000138.5 c.2956G>A is a missense variant in FBN1 predicted to cause a substitution of an alanine by a threonine at amino acid 986 (p.Ala986Thr). This variant has been identified in numerous individuals with diagnoses or suspicion of Marfan syndrome in both the published literature and internal databases (PP4; PMIDs: 24793577, 26410935, 27582083, 28679693, 28387797; Bichat, Mayo, UZG, UZA); however, in at least 3 of these cases, another pathogenic variant in FBN1 was also present (BP2; Bichat). This variant has been previously reported in ClinVar as likely benign or benign by more than 20 laboratories (Variation ID: 36060). It is present in gnomAD v2.1.1 at a frequency of 0.19% (245/129170 alleles) in the European sub-population (BA1; https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analysis are unclear about a predicted impact of this variant. In summary, this variant meets criteria to be classified as benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BA1, BP2, PP4. The pathogenic evidence code PP4 was not considered to be in conflict with this conclusion.

#	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 8, 2024

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