NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys) AND Glomerulopathy with fibronectin deposits 2

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 10, 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:: RCV000017722.31

Allele description [Variation Report for NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)]

NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)

Gene:

FN1:fibronectin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_212482.4(FN1):c.2918A>G (p.Tyr973Cys)

Other names:

Y983C

HGVS:

NC_000002.12:g.215406306T>C
NG_012196.1:g.34763A>G
NM_001306129.2:c.2918A>G
NM_001306130.2:c.2918A>G
NM_001306131.2:c.2918A>G
NM_001306132.2:c.2918A>G
NM_001365517.2:c.2918A>G
NM_001365518.2:c.2918A>G
NM_001365519.2:c.2918A>G
NM_001365520.2:c.2918A>G
NM_001365521.2:c.2918A>G
NM_001365522.2:c.2918A>G
NM_001365523.2:c.2918A>G
NM_001365524.2:c.2918A>G
NM_002026.4:c.2918A>G
NM_212474.3:c.2918A>G
NM_212476.3:c.2918A>G
NM_212478.3:c.2918A>G
NM_212482.4:c.2918A>GMANE SELECT
NP_001293058.2:p.Tyr973Cys
NP_001293059.2:p.Tyr973Cys
NP_001293060.2:p.Tyr973Cys
NP_001293061.2:p.Tyr973Cys
NP_001352446.1:p.Tyr973Cys
NP_001352447.1:p.Tyr973Cys
NP_001352448.1:p.Tyr973Cys
NP_001352449.1:p.Tyr973Cys
NP_001352450.1:p.Tyr973Cys
NP_001352451.1:p.Tyr973Cys
NP_001352452.1:p.Tyr973Cys
NP_001352453.1:p.Tyr973Cys
NP_002017.2:p.Tyr973Cys
NP_997639.2:p.Tyr973Cys
NP_997641.2:p.Tyr973Cys
NP_997643.2:p.Tyr973Cys
NP_997647.1:p.Tyr973Cys
NP_997647.2:p.Tyr973Cys
NC_000002.11:g.216271029T>C
NM_212482.3:c.2918A>G
P02751:p.Tyr973Cys

Protein change:

Y973C; TYR983CYS

Links:

UniProtKB: P02751#VAR_043918; OMIM: 135600.0003; dbSNP: rs137854488

NCBI 1000 Genomes Browser:

rs137854488

Molecular consequence:

NM_001306129.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306130.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306131.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001306132.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365517.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365518.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365519.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365520.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365521.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365522.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365523.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001365524.2:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002026.4:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_212474.3:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_212476.3:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_212478.3:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_212482.4:c.2918A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Glomerulopathy with fibronectin deposits 2 (GFND2)
Synonyms:: Glomerular nephritis familial with fibronectin deposits
Identifiers:: MONDO: MONDO:0011165; MedGen: C1866075; Orphanet: 84090; OMIM: 601894

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000037999	OMIM	no assertion criteria provided	Pathogenic (Feb 19, 2008)	germline	literature only	PubMed (4) [See all records that cite these PMIDs] 18268355, 1544672, 7747733, 12042895
SCV001427189	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 10, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000037999

OMIM

no assertion criteria provided

Pathogenic
(Feb 19, 2008)

germline

literature only

PubMed (4)
[See all records that cite these PMIDs]

SCV001427189

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 10, 2019)

unknown

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Mutations in FN1 cause glomerulopathy with fibronectin deposits.

Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M, Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M.

Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2538-43. doi: 10.1073/pnas.0707730105. Epub 2008 Feb 11.

PubMed [citation]

PMID:: 18268355
PMCID:: PMC2268172

Glomerulonephritis with organized deposits: a mesangiopathic, not immune complex-mediated disease? A pathologic study of two cases in the same family.

Mazzucco G, Maran E, Rollino C, Monga G.

Hum Pathol. 1992 Jan;23(1):63-8.

PubMed [citation]

PMID:: 1544672

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000037999.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (4)

Description

In affected members of 4 unrelated families with glomerulopathy with fibronectin deposits (601894), Castelletti et al. (2008) identified a heterozygous 2918A-G transition in the FN1 gene, resulting in a tyr973-to-cys (Y983C) substitution in the III-4 repeat in the HepIII heparin-binding domain. Three of the families had previously been reported by Mazzucco et al. (1992), Assmann et al. (1995), and Niimi et al. (2002). The 4 families were of different ethnic origin and did not share a disease haplotype, thus excluding a founder effect.

#	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		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001427189.2

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

Description

A heterozygous missense variant, NM_212482.3(FN1):c.2918A>G, has been identified in exon 19 of 46 of the FN1 gene (NB: This variant is non-coding in alternative transcripts). The variant is predicted to result in a major amino acid change from tyrosine to cysteine at position 973 of the protein (NP_997647.1(FN1):p.(Tyr973Cys)). The tyrosine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the Hep III heparin-binding domain (Castelletti, F., et al. (2008)) and fibronectin type III functional domain. In silico predictions for this variant are consistently pathogenic (Polyphen, SIFT, CADD, Mutation Taster). The variant is absent in the gnomAD population database. The variant has been previously described as pathogenic and segregated with disease in multiple families with glomerulopathy with fibronectin deposits (ClinVar, Ohtsubo, H., et al. (2016), Ertoy Baydar, D., et al. (2013)). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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

Last Updated: Jul 29, 2023

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