NM_000138.5(FBN1):c.299G>A (p.Cys100Tyr) AND Marfan syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 24, 2022
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:: RCV000220364.7

Allele description [Variation Report for NM_000138.5(FBN1):c.299G>A (p.Cys100Tyr)]

NM_000138.5(FBN1):c.299G>A (p.Cys100Tyr)

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.299G>A (p.Cys100Tyr)

HGVS:

NC_000015.10:g.48610775C>T
NG_008805.2:g.40014G>A
NM_000138.5:c.299G>AMANE SELECT
NP_000129.3:p.Cys100Tyr
NP_000129.3:p.Cys100Tyr
LRG_778t1:c.299G>A
LRG_778:g.40014G>A
LRG_778p1:p.Cys100Tyr
NC_000015.9:g.48902972C>T
NM_000138.4:c.299G>A

Protein change:

C100Y

Links:

dbSNP: rs397515782

NCBI 1000 Genomes Browser:

rs397515782

Molecular consequence:

NM_000138.5:c.299G>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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ALAD aminolevulinate dehydratase [Homo sapiens]
ALAD aminolevulinate dehydratase [Homo sapiens]
Gene ID:210

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Gene Links for GEO Profiles (Select 126384962) (1)
Gene
WDR31 WD repeat domain 31 [Homo sapiens]
WDR31 WD repeat domain 31 [Homo sapiens]
Gene ID:114987

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Gene Links for GEO Profiles (Select 126384428) (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271224	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 4, 2015)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19533785, 10486319, 24033266
SCV002557757	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jun 24, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19533785, 20301510, 27274304, 29357934, 31227806, 31730815, 31950671, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271224

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 4, 2015)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002557757

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jun 24, 2022)

germline

clinical testing

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

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes.

Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U.

Am J Hum Genet. 1999 Oct;65(4):1007-20.

PubMed [citation]

PMID:: 10486319
PMCID:: PMC1288233

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271224.2

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

Description

The p.Cys100Tyr variant in FBN1 has been identified in 1 African American indivi dual with Marfan syndrome, 1 Chinese individual with Marfan syndrome, and segreg ated with disease in 1 affected relative (LMM unpublished data, Chung 2009). It was absent from large population studies. Additionally, another variant at the s ame position (p.Cys100Phe) has been identified to occur de novo in 1 Asian indiv idual with Marfan syndrome (LMM unpublished data), suggesting that a change at t his position may not be tolerated. Computational prediction tools and conservati on analysis suggest that the p.Cys100Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Furthermor e, this variant affects a highly conserved cysteine residue in the EGF-like doma ins, which is a common finding in individuals with Marfan syndrome (Schrijver 19 99). In summary, although additional studies are required to fully establish its clinical significance, the p.Cys100Tyr variant is likely pathogenic.

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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557757.2

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 are commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects 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 reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with 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 cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant affects a well-established functional cysteine residue of an EGF-like domain. Cysteine substitutions in EGF-like domains are commonly disease-causing (PMID: 31227806). (SP) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Alternative changes to phenylalanine and arginine have been described as pathogenic or likely pathogenic in ClinVar and the literature (PMID: 31730815). (SP) 0803 - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been reported likely pathogenic in ClinVar and in the literature in an individual with Marfan syndrome (PMID: 19533785). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. Mother does not have the variant. Father was not tested. (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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 23, 2024

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