NM_000138.5(FBN1):c.2930T>G (p.Met977Arg) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001190471.6

Allele description [Variation Report for NM_000138.5(FBN1):c.2930T>G (p.Met977Arg)]

NM_000138.5(FBN1):c.2930T>G (p.Met977Arg)

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.2930T>G (p.Met977Arg)

HGVS:

NC_000015.10:g.48490003A>C
NG_008805.2:g.160786T>G
NM_000138.5:c.2930T>GMANE SELECT
NP_000129.3:p.Met977Arg
NP_000129.3:p.Met977Arg
LRG_778t1:c.2930T>G
LRG_778:g.160786T>G
LRG_778p1:p.Met977Arg
NC_000015.9:g.48782200A>C
NM_000138.4:c.2930T>G

Protein change:

M977R

Links:

dbSNP: rs199682686

NCBI 1000 Genomes Browser:

rs199682686

Molecular consequence:

NM_000138.5:c.2930T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

Recent activity

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PREDICTED: Gallus gallus family with sequence similarity 3 member B (FAM3B), tra...
PREDICTED: Gallus gallus family with sequence similarity 3 member B (FAM3B), transcript variant X2, mRNA
gi|2201570957|ref|XM_416736.7|

Nucleotide
LOC117414667 [Acipenser ruthenus]
LOC117414667 [Acipenser ruthenus]
Gene ID:117414667

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001357970	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25652356, 25741868
SCV002752409	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Feb 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001357970

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 21, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV002752409

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Feb 17, 2021)

germline

clinical testing

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

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

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

Decreased frequency of FBN1 missense variants in Ghent criteria-positive Marfan syndrome and characterization of novel FBN1 variants.

Baudhuin LM, Kotzer KE, Lagerstedt SA.

J Hum Genet. 2015 May;60(5):241-52. doi: 10.1038/jhg.2015.10. Epub 2015 Feb 5.

PubMed [citation]

PMID:: 25652356

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001357970.3

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

Description

This missense variant replaces methionine with arginine at codon 977 of the FBN1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Marfan syndrome (PMID: 25652356). This variant has been identified in 4/251462 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.

#	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 Ambry Genetics, SCV002752409.2

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

Description

The p.M977R variant (also known as c.2930T>G), located in coding exon 24 of the FBN1 gene, results from a T to G substitution at nucleotide position 2930. The methionine at codon 977 is replaced by arginine, an amino acid with similar properties, and is located in the TGFBP #03 domain. This alteration was reported in a subject with features of Marfan syndrome who did not meet Ghent criteria (Baudhuin LM et al. J Hum Genet, 2015 May;60:241-52). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	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

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