VCV003255147.1 - ClinVar

NM_212482.4(FN1):c.7229G>A (p.Cys2410Tyr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(1)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_212482.4(FN1):c.7229G>A (p.Cys2410Tyr)

Variation ID: 3255147 Accession: VCV003255147.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q35 2: 215364901 (GRCh38) [ NCBI UCSC ] 2: 216229624 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 23, 2024	Jul 23, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_212482.4:c.7229G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_997647.2:p.Cys2410Tyr	missense
NM_001306129.2:c.7136G>A	NP_001293058.2:p.Cys2379Tyr	missense
NM_001306130.2:c.6599G>A	NP_001293059.2:p.Cys2200Tyr	missense
NM_001306131.2:c.6593G>A	NP_001293060.2:p.Cys2198Tyr	missense
NM_001306132.2:c.6518G>A	NP_001293061.2:p.Cys2173Tyr	missense
NM_001365517.2:c.6959G>A	NP_001352446.1:p.Cys2320Tyr	missense
NM_001365518.2:c.6956G>A	NP_001352447.1:p.Cys2319Tyr	missense
NM_001365519.2:c.6884G>A	NP_001352448.1:p.Cys2295Tyr	missense
NM_001365520.2:c.6881G>A	NP_001352449.1:p.Cys2294Tyr	missense
NM_001365521.2:c.6866G>A	NP_001352450.1:p.Cys2289Tyr	missense
NM_001365522.2:c.6791G>A	NP_001352451.1:p.Cys2264Tyr	missense
NM_001365523.2:c.6611G>A	NP_001352452.1:p.Cys2204Tyr	missense
NM_001365524.2:c.6596G>A	NP_001352453.1:p.Cys2199Tyr	missense
NM_002026.4:c.6863G>A	NP_002017.2:p.Cys2288Tyr	missense
NM_212474.3:c.6326G>A	NP_997639.2:p.Cys2109Tyr	missense
NM_212476.3:c.6686G>A	NP_997641.2:p.Cys2229Tyr	missense
NM_212478.3:c.6788G>A	NP_997643.2:p.Cys2263Tyr	missense
NC_000002.12:g.215364901C>T
NC_000002.11:g.216229624C>T
NG_012196.1:g.76168G>A
NG_012196.2:g.76167G>A

... more HGVS ... less HGVS

Protein change

C2109Y, C2173Y, C2198Y, C2199Y, C2200Y, C2204Y, C2229Y, C2263Y, C2264Y, C2288Y, C2289Y, C2294Y, C2295Y, C2319Y, C2320Y, C2379Y, C2410Y

Other names

Canonical SPDI

NC_000002.12:215364900:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ATIC		-	-	GRCh38 GRCh37	118	279
FN1		-	-	GRCh38 GRCh37	1071	1424

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Glomerulopathy with fibronectin deposits 2	Uncertain significance (1)	criteria provided, single submitter	Jul 17, 2023	RCV004595330.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Glomerulopathy with fibronectin deposits 2 (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086505.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (2) PubMed: 29100092‚ 32200603 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function has been suggested based on mutant proteins not being secreted and subsequent intracellular accumulation (PMID: 29100092). (I) 0107 - This gene is associated with autosomal dominant disease. Variants associated with glomerulopathy with fibronectin deposits 2 (MIM#601894) lie within the C-terminus, while variants associated with spondylometaphyseal dysplasia, corner fracture type (MIM#184255) lie within the N-terminus and often affect the cysteine residues involved in disulphide bonds (PMIDs: 29100092, 32200603). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been observed (PMID: 32200603). (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) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated fibronectin type 1 domain at the C-terminus and affects a cysteine residue involved in a disulphide bond (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. However, loss of function has been suggested based on mutant proteins not being secreted and subsequent intracellular accumulation (PMID: 29100092). (I) 0107 - This gene is associated with autosomal dominant disease. Variants associated with glomerulopathy with fibronectin deposits 2 (MIM#601894) lie within the C-terminus, while variants associated with spondylometaphyseal dysplasia, corner fracture type (MIM#184255) lie within the N-terminus and often affect the cysteine residues involved in disulphide bonds (PMIDs: 29100092, 32200603). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been observed (PMID: 32200603). (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) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated fibronectin type 1 domain at the C-terminus and affects a cysteine residue involved in a disulphide bond (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Spondylometaphyseal Dysplasia, Corner Fracture Type.	Adam MP	-	2020	PMID: 32200603
Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with "Corner Fractures".	Lee CS	American journal of human genetics	2017	PMID: 29100092

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_212482.4(FN1):c.7229G>A (p.Cys2410Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...