NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn) AND Marfan syndrome

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 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:: RCV003333037.4

Allele description [Variation Report for NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)]

NM_000138.5(FBN1):c.3463G>A (p.Asp1155Asn)

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.3463G>A (p.Asp1155Asn)

Other names:

p.D1155N:GAC>AAC

HGVS:

NC_000015.10:g.48487312C>T
NG_008805.2:g.163477G>A
NM_000138.5:c.3463G>AMANE SELECT
NP_000129.3:p.Asp1155Asn
NP_000129.3:p.Asp1155Asn
LRG_778t1:c.3463G>A
LRG_778:g.163477G>A
LRG_778p1:p.Asp1155Asn
NC_000015.9:g.48779509C>T
NM_000138.4:c.3463G>A

Protein change:

D1155N

Links:

dbSNP: rs794728204

NCBI 1000 Genomes Browser:

rs794728204

Molecular consequence:

NM_000138.5:c.3463G>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
SCV004041194	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004814801	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Jul 19, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 8941093, 9452033, 14695540, 17657824, 19293843, 20564469, 32679894, 25741868
SCV005086277	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 14695540, 20301510, 27274304, 29357934, 31950671, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004041194

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 18, 2023)

unknown

clinical testing

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

SCV004814801

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Jul 19, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV005086277

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (6)
[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	1	not provided	not provided	108544	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms.

Milewicz DM, Michael K, Fisher N, Coselli JS, Markello T, Biddinger A.

Circulation. 1996 Dec 1;94(11):2708-11.

PubMed [citation]

PMID:: 8941093

Two novel fibrillin-1 mutations resulting in premature termination codons but in different mutant transcript levels and clinical phenotypes.

Karttunen L, Ukkonen T, Kainulainen K, Syvänen AC, Peltonen L.

Hum Mutat. 1998;Suppl 1:S34-7. No abstract available.

PubMed [citation]

PMID:: 9452033

See all PubMed Citations (12)

Details of each submission

From Baylor Genetics, SCV004041194.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	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, SCV004814801.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces aspartic acid with asparagine at codon 1155 in the EGF-like calcium-binding domain of the FBN1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that cells expressing the mutant protein deposit a decreased amount of fibrillin protein into deposit extracellular matrix compared to control cells (PMID: 8941093). In addition, this variant alters the conserved, last c.G nucleotide of exon 28 and is predicted to affect RNA splicing. RNA studies have produced conflicting results. While one RT-PCR study of patient fibroblasts did not show RNA splicing defect (PMID: 8941093), another study has revealed a 111 bp-insertion in the FBN1 transcript due to the retention of intronic sequence, resulting in the introduction of a premature protein truncation codon (PMID: 9452033). The mutant transcript with the intronic sequence retention represented 22% of total FBN1 mRNA. This variant has been reported in four individuals affected with Marfan syndrome (PMID: 9452033, 14695540, 19293843, 32679894), one individual affected individual with thoracic aortic aneurysm (PMID: 8941093) and two individuals affected with ectopia lentis (PMID: 17657824, 20564469). This variant has been identified in 1/31402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086277.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been rarely reported (PMID: 27274304; 31950671). (I) 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated calcium-binding EGF domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two alternative changes, p.(Asp1155Val) and p.(Asp1155Gly), have been submitted to ClinVar once each as likely pathogenic. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and has been observed in individuals with Marfan syndrome, ectopia lentis, aortic disease and/or striae atrophica with inguinal or umbilical herniae (ClinVar, PMID: 14695540). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Dec 22, 2024

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