NM_000138.5(FBN1):c.4001G>A (p.Gly1334Asp) AND Marfan syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 18, 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:: RCV001839446.11

Allele description [Variation Report for NM_000138.5(FBN1):c.4001G>A (p.Gly1334Asp)]

NM_000138.5(FBN1):c.4001G>A (p.Gly1334Asp)

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.4001G>A (p.Gly1334Asp)

HGVS:

NC_000015.10:g.48474614C>T
NG_008805.2:g.176175G>A
NM_000138.5:c.4001G>AMANE SELECT
NP_000129.3:p.Gly1334Asp
NP_000129.3:p.Gly1334Asp
LRG_778t1:c.4001G>A
LRG_778:g.176175G>A
LRG_778p1:p.Gly1334Asp
NC_000015.9:g.48766811C>T
NM_000138.4:c.4001G>A
c.4001G>A

Protein change:

G1334D

Links:

dbSNP: rs191989961

NCBI 1000 Genomes Browser:

rs191989961

Molecular consequence:

NM_000138.5:c.4001G>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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Nucleotide
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gi|610492273|gb|KJ553683.1|

Nucleotide
PREDICTED: neutrophil cytosol factor 2 isoform X1 [Bos mutus]
PREDICTED: neutrophil cytosol factor 2 isoform X1 [Bos mutus]
gi|942047464|ref|XP_014332873.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001622851	New York Genome Center - CSER-NYCKidSeq	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jan 29, 2021)	inherited	clinical testing	Citation Link,
SCV004814767	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24793577, 26214305, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001622851

New York Genome Center - CSER-NYCKidSeq

criteria provided, single submitter

(NYGC Assertion Criteria 2020)

Uncertain significance
(Jan 29, 2021)

inherited

clinical testing

Citation Link,

SCV004814767

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Dec 18, 2023)

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	10	not provided	not provided	108544	not provided	clinical testing
not provided	inherited	unknown	2	not provided	not provided	2	not provided	clinical testing

Citations

PubMed

The spectrum of FBN1, TGFβR1, TGFβR2 and ACTA2 variants in 594 individuals with suspected Marfan Syndrome, Loeys-Dietz Syndrome or Thoracic Aortic Aneurysms and Dissections (TAAD).

Lerner-Ellis JP, Aldubayan SH, Hernandez AL, Kelly MA, Stuenkel AJ, Walsh J, Joshi VA.

Mol Genet Metab. 2014 Jun;112(2):171-6. doi: 10.1016/j.ymgme.2014.03.011. Epub 2014 Apr 2.

PubMed [citation]

PMID:: 24793577

Development of a Targeted Multi-Disorder High-Throughput Sequencing Assay for the Effective Identification of Disease-Causing Variants.

Delio M, Patel K, Maslov A, Marion RW, McDonald TV, Cadoff EM, Golden A, Greally JM, Vijg J, Morrow B, Montagna C.

PLoS One. 2015;10(7):e0133742. doi: 10.1371/journal.pone.0133742.

PubMed [citation]

PMID:: 26214305
PMCID:: PMC4516357

See all PubMed Citations (3)

Details of each submission

From New York Genome Center - CSER-NYCKidSeq, SCV001622851.2

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

Description

The inherited c.4001G>A (p.Gly1334Asp) variant identified in the FBN1 gene substitutes a moderately conserved Glycine for Aspartic Acid at amino acid 1334/2872 (coding exon 33/66). This variant is found in 20 heterozygotes and 0 homozygotes in gnomAD(v3.1) with an allele frequency of 1.32e-4. In silico algorithms predict this variant to be Neutral (Provean; score: 3.75) and Tolerated (SIFT; score: 1.00) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:42345), including a submission by one clinical lab in which this variant was identified in a family with features of Marfan syndrome. The p.Gly1334Asp variant identified here has also been reported in the literature in a family with Marfan syndrome like features, ticks, possible Tourette Syndrome, speech delay and fine motor delay [PMID:26214305]. The p.Gly1334 residue is within one of the EGF-like calcium binding domains of FBN1 (UniProtKB:P35555). While it has been observed in affected individuals in the literature, the presence of 20 heterozygotes in gnomAD(v3.1) is higher than expected for autosomal dominant Marfan Syndrome. Given this, the inherited c.4001G>A (p.Gly1334Asp) variant identified in the FBN1 gene is reported as a Variant of Uncertain Significance.

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

From All of Us Research Program, National Institutes of Health, SCV004814767.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces glycine with aspartic acid at codon 1334 of the FBN1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals with Marfan syndrome-like features (PMID: 24793577, 26214305). Two of these individuals were twin siblings who were also affected with multiple other congenital abnormalities (PMID: 26214305). This variant has been observed to co-occur with another FBN1 variant (c.1006T>C, p.Cys336Arg) in an adolescent individual affected with Marfan syndrome ( doi:10.1164/ajrccm-conference.2022.205.1_MeetingAbstracts.A2052). This variant has been identified in 2/251238 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	108544	not provided	not provided		10	not provided	not provided	not provided

Last Updated: Aug 25, 2024

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