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Skeletal dysplasia

Gene: ZNF687

Amber List (moderate evidence)

ZNF687 (zinc finger protein 687)
EnsemblGeneIds (GRCh38): ENSG00000143373
EnsemblGeneIds (GRCh37): ENSG00000143373
OMIM: 610568, Gene2Phenotype
ZNF687 is in 1 panel

2 reviews

Eleanor Williams (Genomics England Curator)

Green List (high evidence)

Comment on list classification: Promoting from grey to amber but with a recommendation for a green rating following GMS review.
Created: 10 Nov 2021, 10:49 a.m. | Last Modified: 10 Nov 2021, 10:49 a.m.
Panel Version: 2.152
Associated with Paget disease of bone 6 #616833 (AD) in OMIM. Paget's disease of bone (PDB) is a bone disorder characterized by focal areas of increased bone resorption coupled with a disorganized increase in bone formation (from PMID: 29493781). In some cases PDB is also associated with giant cell tumor (GCT).

Founder variant c.2810C>G (p.Pro937Arg) associated with PDB/GCT in many families from Southern Italy, but also in one family with a different haplotype. 3 other different variants have also been identified in this gene in 2 sporadic and 1 familial case of PDB.

PMID: 29493781 - Divisato et al 2018 - report 10 out of 30 of patients with PDB recruited from Avellino, Southern Italy with ZNF687 variants. In all familial cases (8 patients) the p.Pro937Arg variant was found. 2 novel mutations c.1994C>T, p.Pro665Leu and c.2350C>G, p.Gln784Glu were also found in two sporadic cases with a milder phenotype and later onset (55 years and 63 years, respectively). The patients with the p.Pro937Arg variant had the same allelic composition while those with the other two variants had a different haplotype.

PMID: 26849110 - Divisato et al 2016 - using WES they identified a heterozygous c.2810C>G (p.Pro937Arg) missense variant that segregated with the clinical phenotype in a family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites. No variants were found in other PDB-related/PDB similar syndrome genes (SQSTM1, TNFRSF11A, TNFRSF11B, VCP). The c.2810C>G variant was then found in 7 additional unrelated individuals with PDB complicated with GCT, 4 from the same area of Southern Italy as family 1, and 3 were North-American individuals of European descent. All but 1 were found to have identical variants in surrounding genes (i.e. same haplotype) but the occurrence of the c.2810C>G mutation on a different haplotype in one individual provides the genetic evidence that this mutation is likely causative. In addition, another variant in ZNF687 (c.725G>T (p.Ser242Ile)) was found in 4 affected individuals in another family, but not in 3 unaffected family members.

Also mentioned by reviewer - PMID: 28968976 - Divisato et al 2017 - identify H3F3A mutations in a giant cell tumor (GCT) cohort but no mutations in the ZNF687 gene were found in these patients.
Created: 10 Nov 2021, 10:48 a.m. | Last Modified: 10 Nov 2021, 10:48 a.m.
Panel Version: 2.151

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Paget disease of bone 6, OMIM:616833

Publications

Adrienne Flanagan (Royal National Orthopaedic Hospital)

Green List (high evidence)

Missense mutation c.2810C>G (p.Pro937Arg) alters the nuclear-ctyoplasmic balance of ZNF687 by generating a stronger nuclear localisation signal thereby acting as a gain-of-function mutation.
Sources: Other, Research
Created: 26 Oct 2021, 1:29 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Paget Disease of Bone with associated Giant Cell Tumour.

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • Paget disease of bone 6, OMIM:616833
Tags
Q4_21_rating Q4_21_NHS_review
OMIM
610568
Clinvar variants
Variants in ZNF687
Penetrance
unknown
Publications
Mode of Pathogenicity
Other
Panels with this gene

History Filter Activity

13 Dec 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q4_21_NHS_review tag was added to gene: ZNF687.

10 Nov 2021, Gel status: 2

Set Phenotypes

Eleanor Williams (Genomics England Curator)

Phenotypes for gene: ZNF687 were changed from Paget Disease of Bone with associated Giant Cell Tumour. to Paget disease of bone 6, OMIM:616833

10 Nov 2021, Gel status: 2

Set publications

Eleanor Williams (Genomics England Curator)

Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110

10 Nov 2021, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: znf687 has been classified as Amber List (Moderate Evidence).

10 Nov 2021, Gel status: 0

Added Tag

Eleanor Williams (Genomics England Curator)

Tag Q4_21_rating tag was added to gene: ZNF687.

26 Oct 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Adrienne Flanagan (Royal National Orthopaedic Hospital)

gene: ZNF687 was added gene: ZNF687 was added to Skeletal dysplasia. Sources: Other,Research Mode of inheritance for gene: ZNF687 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ZNF687 were set to PMID: 29493781, PMID: 28968976, PMID: 26849110 Phenotypes for gene: ZNF687 were set to Paget Disease of Bone with associated Giant Cell Tumour. Penetrance for gene: ZNF687 were set to unknown Mode of pathogenicity for gene: ZNF687 was set to Other Review for gene: ZNF687 was set to GREEN