NM_000138.5(FBN1):c.5783G>A (p.Cys1928Tyr) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 30, 2024
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:: RCV000506228.9

Allele description [Variation Report for NM_000138.5(FBN1):c.5783G>A (p.Cys1928Tyr)]

NM_000138.5(FBN1):c.5783G>A (p.Cys1928Tyr)

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.5783G>A (p.Cys1928Tyr)

HGVS:

NC_000015.10:g.48446711C>T
NG_008805.2:g.204078G>A
NM_000138.5:c.5783G>AMANE SELECT
NP_000129.3:p.Cys1928Tyr
NP_000129.3:p.Cys1928Tyr
LRG_778t1:c.5783G>A
LRG_778:g.204078G>A
LRG_778p1:p.Cys1928Tyr
NC_000015.9:g.48738908C>T
NM_000138.4:c.5783G>A
NM_000138.5:c.5783G>A

Protein change:

C1928Y

Links:

dbSNP: rs587782947

NCBI 1000 Genomes Browser:

rs587782947

Molecular consequence:

NM_000138.5:c.5783G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000603667	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (May 5, 2017)	germline	clinical testing	Citation Link,
SCV005078320	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 30, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000603667

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(May 5, 2017)

germline

clinical testing

Citation Link,

SCV005078320

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 30, 2024)

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000603667.2

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

Description

The p.Cys1928Tyr variant has been identified in association with Marfan syndrome in several unrelated individuals (Rommel 2005 and Stheneur 2009). The p.Cys1928Tyr variant disrupts a cysteine residue in an EGF domain which meets the criteria for a causative variant according to the revised Ghent nosology. (Loeys 2010). It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. Based on these observations, the p.Cys1928Tyr variant has been classified as pathogenic.

#	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

From GeneDx, SCV005078320.1

#	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, including one de novo occurrence and one individual with a similarly affected daughter who also harbors the variant (PMID: 16220557, 19293843); 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 (PMID: 12938084); 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: 12938084, 19293843, 16220557)

#	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: Nov 10, 2024

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