NM_000138.5(FBN1):c.2216G>A (p.Cys739Tyr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 7, 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:: RCV000622311.3

Allele description [Variation Report for NM_000138.5(FBN1):c.2216G>A (p.Cys739Tyr)]

NM_000138.5(FBN1):c.2216G>A (p.Cys739Tyr)

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.2216G>A (p.Cys739Tyr)

HGVS:

NC_000015.10:g.48497343C>T
NG_008805.2:g.153446G>A
NM_000138.5:c.2216G>AMANE SELECT
NP_000129.3:p.Cys739Tyr
NP_000129.3:p.Cys739Tyr
LRG_778t1:c.2216G>A
LRG_778:g.153446G>A
LRG_778p1:p.Cys739Tyr
NC_000015.9:g.48789540C>T
NM_000138.4:c.2216G>A

Protein change:

C739Y

Links:

dbSNP: rs1555399378

NCBI 1000 Genomes Browser:

rs1555399378

Molecular consequence:

NM_000138.5:c.2216G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: CN517202

Recent activity

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Homo sapiens methionine adenosyltransferase 2A (MAT2A), mRNA
Homo sapiens methionine adenosyltransferase 2A (MAT2A), mRNA
gi|336595075|ref|NM_005911.5|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000740512	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845913	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 7, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000740512

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 3, 2017)

germline

clinical testing

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

SCV003845913

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 7, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	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 Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000740512.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV003845913.1

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

Description

Identified in patients with Marfan syndrome in published literature (Franken et al., 2016; Fang et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Affects a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene, which may affect disulfide bonding and is predicted to alter the structure and function of the protein; cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with FBN1-related disorders (Collod-Beroud et al., 2003); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26787436, 12938084, 28855619)

#	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: Jun 24, 2023

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