NM_000138.5(FBN1):c.902G>T (p.Gly301Val) AND not specified

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Dec 27, 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:: RCV000181419.22

Allele description [Variation Report for NM_000138.5(FBN1):c.902G>T (p.Gly301Val)]

NM_000138.5(FBN1):c.902G>T (p.Gly301Val)

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.902G>T (p.Gly301Val)

Other names:

p.G301V:GGG>GTG

HGVS:

NC_000015.10:g.48526216C>A
NG_008805.2:g.124573G>T
NM_000138.5:c.902G>TMANE SELECT
NP_000129.3:p.Gly301Val
NP_000129.3:p.Gly301Val
LRG_778t1:c.902G>T
LRG_778:g.124573G>T
LRG_778p1:p.Gly301Val
NC_000015.9:g.48818413C>A
NM_000138.4:c.902G>T
p.Gly301Val

Protein change:

G301V

Links:

dbSNP: rs142888621

NCBI 1000 Genomes Browser:

rs142888621

Molecular consequence:

NM_000138.5:c.902G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001361427	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Dec 27, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26188975, 26787436, 28655553, 25613431 Citation Link,
SCV001365724	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jan 2, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26188975, 26787436, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001361427

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Dec 27, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001365724

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jan 2, 2019)

germline

clinical testing

PubMed (3)
[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	2	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.

Mattassi R, Manara E, Colombo PG, Manara S, Porcella A, Bruno G, Bruson A, Bertelli M.

J Vasc Surg. 2018 Mar;67(3):922-932.e11. doi: 10.1016/j.jvs.2017.02.034. Epub 2017 Jun 24.

PubMed [citation]

PMID:: 28655553

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

Franken R, den Hartog AW, Radonic T, Micha D, Maugeri A, van Dijk FS, Meijers-Heijboer HE, Timmermans J, Scholte AJ, van den Berg MP, Groenink M, Mulder BJ, Zwinderman AH, de Waard V, Pals G.

Circ Cardiovasc Genet. 2015 Apr;8(2):383-8. doi: 10.1161/CIRCGENETICS.114.000950. Epub 2015 Jan 22.

PubMed [citation]

PMID:: 25613431

See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001361427.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: FBN1 c.902G>T (p.Gly301Val) results in a non-conservative amino acid change located in the EGF-like repeat domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251426 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3- fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011). c.902G>T has been reported in the literature in individuals affected with symptoms belonging to the Marfan Syndrome phenotype spectrum (e.g. vascular anomalies and ascending aortic aneurysm), however no supporting evidence (e.g. segregation data) for causality was provided (e.g. Mattassi_2018, Franken_2016, Ziganshin_2015). These reports do not provide unequivocal conclusions about association of the variant with Marfan Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25613431, 26787436, 28655553, 26188975). ClinVar contains an entry for this variant (Variation ID: 199960). Based on the evidence outlined above, the variant was 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365724.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

Variant classified as Uncertain Significance - Favor Benign. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Identified in 2 Marfan probands (PubMed: 26787436). Computational tools predict benign. Identified in 0.04% of European chromosoems in gnomAD.

#	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		2	not provided	1	not provided

Last Updated: Jun 22, 2025

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Relating variation to medicine