NM_000138.5(FBN1):c.4291T>C (p.Cys1431Arg) AND Marfan syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Apr 16, 2019
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:: RCV004018084.1

Allele description [Variation Report for NM_000138.5(FBN1):c.4291T>C (p.Cys1431Arg)]

NM_000138.5(FBN1):c.4291T>C (p.Cys1431Arg)

Genes:

LOC126862124:CDK7 strongly-dependent group 2 enhancer GRCh37_chr15:48764566-48765765 [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.4291T>C (p.Cys1431Arg)

HGVS:

NC_000015.10:g.48472596A>G
NG_008805.2:g.178193T>C
NG_086622.1:g.328A>G
NM_000138.5:c.4291T>CMANE SELECT
NM_001406716.1:c.4291T>C
NP_000129.3:p.Cys1431Arg
NP_000129.3:p.Cys1431Arg
NP_001393645.1:p.Cys1431Arg
LRG_778t1:c.4291T>C
LRG_778:g.178193T>C
LRG_778p1:p.Cys1431Arg
NC_000015.9:g.48764793A>G
NM_000138.4:c.4291T>C

Protein change:

C1431R

Molecular consequence:

NM_000138.5:c.4291T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406716.1:c.4291T>C - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

Clear Turn Off Turn On

Taraxacum tanylepis (3725)
Protein
3'-5' exonuclease [Methanosphaerula palustris]
3'-5' exonuclease [Methanosphaerula palustris]
gi|501693943|ref|WP_012618903.1|

Protein
F0F1 ATP synthase subunit beta [Sulfuricurvum kujiense]
F0F1 ATP synthase subunit beta [Sulfuricurvum kujiense]
gi|503224961|ref|WP_013459622.1|

Protein
Homo sapiens ATPase H+ transporting V0 subunit d1 (ATP6V0D1), RefSeqGene on chro...
Homo sapiens ATPase H+ transporting V0 subunit d1 (ATP6V0D1), RefSeqGene on chromosome 16
gi|224809278|ref|NG_011482.1|

Nucleotide
1131516[uid] (1)
Taxonomy

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847710	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 16, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24161884, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847710

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Apr 16, 2019)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Relation between genotype and left-ventricular dilatation in patients with Marfan syndrome.

Aalberts JJ, van Tintelen JP, Meijboom LJ, Polko A, Jongbloed JD, van der Wal H, Pals G, Osinga J, Timmermans J, de Backer J, Bakker MK, van Veldhuisen DJ, Hofstra RM, Mulder BJ, van den Berg MP.

Gene. 2014 Jan 15;534(1):40-3. doi: 10.1016/j.gene.2013.10.033. Epub 2013 Oct 24.

PubMed [citation]

PMID:: 24161884

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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847710.1

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

Description

The p.Cys1431Arg variant in FBN1 has been identified in at least 1 individual with Marfan syndrome (Aalberts 2014) and was absent from large population studies. This variant affects a cysteine residue; cysteine substitutions are a common finding in individuals with Marfan syndrome (Schrijver, 1999). Two other variants involving this residue, p.Cys1431Trp and p.Cys1431Tyr, have been associated with Marfan syndrome (Baetens 2011), suggesting that changes at this position are not tolerated. Computational prediction tools and conservation analysis suggest that the p.Cys1431Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Marfan syndrome. ACMG/AMP Criteria applied: PM1; PM2; PP3; PS4_Supporting.

#	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: May 7, 2024

ClinVar

Relating variation to medicine