NM_000138.5(FBN1):c.3083A>G (p.Asp1028Gly) AND Marfan syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 31, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003444556.1

Allele description [Variation Report for NM_000138.5(FBN1):c.3083A>G (p.Asp1028Gly)]

NM_000138.5(FBN1):c.3083A>G (p.Asp1028Gly)

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.3083A>G (p.Asp1028Gly)

HGVS:

NC_000015.10:g.48488493T>C
NG_008805.2:g.162296A>G
NM_000138.5:c.3083A>GMANE SELECT
NP_000129.3:p.Asp1028Gly
NP_000129.3:p.Asp1028Gly
LRG_778t1:c.3083A>G
LRG_778:g.162296A>G
LRG_778p1:p.Asp1028Gly
NC_000015.9:g.48780690T>C
NM_000138.4:c.3083A>G

Protein change:

D1028G

Links:

dbSNP: rs1131691317

NCBI 1000 Genomes Browser:

rs1131691317

Molecular consequence:

NM_000138.5:c.3083A>G - 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
SCV001468417	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 31, 2023)	de novo	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

SCV001468417

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 31, 2023)

de novo

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	de novo	unknown	1	1	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

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV001468417.3

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

Description

This variant has been reported in the literature in two individuals with features suggestive of or consistent with Marfan syndrome, including one individual with ectopia lentis (Comeglio 2007 PMID: 17657824; Li 2014 PMID: 25053872). This variant is not present in gnomAD but is present in ClinVar (Variation ID: 429319). Of note, this variant is located within the consensus binding sequence in a calcium-binding epidermal growth factor (cbEGF)-like domain and may impair protein folding or stabilization (Jensen 2005 PMID: 15649891). Evolutionary conservation and computational prediction tools support that it may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic.

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

Last Updated: Oct 13, 2024

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