NM_000138.5(FBN1):c.79G>A (p.Ala27Thr) AND Marfan syndrome

Germline classification:: Benign (3 submissions)
Last evaluated:: Sep 28, 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:: RCV000358510.12

Allele description [Variation Report for NM_000138.5(FBN1):c.79G>A (p.Ala27Thr)]

NM_000138.5(FBN1):c.79G>A (p.Ala27Thr)

Genes:

LOC130057019:ATAC-STARR-seq lymphoblastoid silent region 6417 [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.79G>A (p.Ala27Thr)

Other names:

p.A27T:GCC>ACC; NM_000138.5(FBN1):c.79G>A

HGVS:

NC_000015.10:g.48644691C>T
NG_008805.2:g.6098G>A
NM_000138.5:c.79G>AMANE SELECT
NP_000129.3:p.Ala27Thr
NP_000129.3:p.Ala27Thr
LRG_778t1:c.79G>A
LRG_778:g.6098G>A
LRG_778p1:p.Ala27Thr
NC_000015.9:g.48936888C>T
NM_000138.4:c.79G>A

Protein change:

A27T

Links:

dbSNP: rs25397

NCBI 1000 Genomes Browser:

rs25397

Molecular consequence:

NM_000138.5:c.79G>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
SCV000392734	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV004037322	ClinGen FBN1 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (Assertion Criteria VCEP FBN1 Version 1)	Benign (Sep 28, 2023)	germline	curation	Citation Link,
SCV005426125	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Sep 17, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000392734

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Benign
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV004037322

ClinGen FBN1 Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(Assertion Criteria VCEP FBN1 Version 1)

Benign
(Sep 28, 2023)

germline

curation

Citation Link,

SCV005426125

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Sep 17, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	43	not provided	not provided	143475	not provided	clinical testing, curation

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000392734.3

#	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 in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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 ClinGen FBN1 Variant Curation Expert Panel, ClinGen, SCV004037322.1

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

Description

The NM_000138.5 c.79G>A, is a missense variant in FBN1 predicted to cause a substitution of a alanine acid by threonine at amino acid 27 (p.Ala27Thr). This variant has been previously reported in ClinVar as likely benign and benign (Variation ID: 163486). This variant has been identified in 129/19954 (0.65%) of individuals of East Asian origin (MAF: 0.65%) (BA1; https://gnomad.broadinstitute.org/ version 2.1.1). It has been reported in individuals with thoracic aortic aneurysm and/or dissection, and in individuals with clinical features of Marfan syndrome, however it was considered to be a polymorphism (PMID 26272055, 19839986, 16835936). Computational prediction tools and conservation analysis suggests no impact on the protein (REVEL: 0.097) (BP4). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of two benign arguments, PP2 cannot be used. 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 ClinGenFBN1 VCEP: BA1, BP4.

#	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, SCV005426125.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	43	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	143475	not provided	not provided		43	not provided	not provided	not provided

Last Updated: May 16, 2025

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