This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937Arg). This variant is present in population databases (rs148402804, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Paget disease (PMID: 26849110, 29493781). ClinVar contains an entry for this variant (Variation ID: 222987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ClinVar Genomic variation as it relates to human health
NM_020832.3(ZNF687):c.2810C>G (p.Pro937Arg)
Germline
Classification
Help
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.
(6)
Help
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.
Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
Pathogenic(1); Likely pathogenic(2); Uncertain significance(2)
6
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020832.3(ZNF687):c.2810C>G (p.Pro937Arg)
Variation ID: 222987 Accession: VCV000222987.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1q21.3 1: 151289853 (GRCh38) [ NCBI UCSC ] 1: 151262329 (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 Mar 1, 2016 Aug 4, 2024 Jul 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020832.3:c.2810C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_065883.1:p.Pro937Arg missense NM_001304763.2:c.2810C>G NP_001291692.1:p.Pro937Arg missense NM_001304764.2:c.2810C>G NP_001291693.1:p.Pro937Arg missense NM_020832.2:c.2810C>G NC_000001.11:g.151289853C>G NC_000001.10:g.151262329C>G NG_051575.1:g.13299C>G Q8N1G0:p.Pro937Arg - Protein change
- P937R
- Other names
- -
- Canonical SPDI
- NC_000001.11:151289852:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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.
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0.00060 (G,T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 30x 0.00047
Trans-Omics for Precision Medicine (TOPMed) 0.00053
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054
1000 Genomes Project 0.00060
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|||
| ZNF687 | - | - |
GRCh38 GRCh37 |
376 | 390 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Apr 4, 2024 | RCV000208586.10 | |
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Jul 31, 2024 | RCV002515559.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Paget disease of bone 6
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002017969.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Uncertain significance
(Jan 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003260738.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937Arg). … (more)
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937Arg). This variant is present in population databases (rs148402804, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Paget disease (PMID: 26849110, 29493781). ClinVar contains an entry for this variant (Variation ID: 222987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
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Pathogenic
(Feb 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Paget disease of bone 6
(Autosomal dominant inheritance)
Affected status: no
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002557966.2
First in ClinVar: Aug 08, 2022 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a likely mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a likely mechanism of disease in this gene and is associated with Paget disease of bone 6 (MIM#616833). Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID: 26849110). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - Variant is heterozygous. (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 50 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v3: 66 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated nuclear localization signal (PMID: 29493781). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg937His) variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the Italian population and has been suggested to be a founder mutation (ClinVar, PMID: 26849110, 29493781). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Uncertain significance
(Apr 04, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Paget disease of bone 6
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004809436.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
|
|
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Likely pathogenic
(Jul 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090753.1
First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024 |
|
|
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Pathogenic
(Feb 26, 2016)
|
no assertion criteria provided
Method: literature only
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PAGET DISEASE OF BONE 6
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000264364.1
First in ClinVar: Mar 01, 2016 Last updated: Mar 01, 2016 |
Comment on evidence:
In 9 members of a large multigenerational Italian family with Paget disease of bone-6 (PDB6; 616833) originally reported by Rendina et al. (2004) and studied … (more)
In 9 members of a large multigenerational Italian family with Paget disease of bone-6 (PDB6; 616833) originally reported by Rendina et al. (2004) and studied further by Gianfrancesco et al. (2013), Divisato et al. (2016) identified a heterozygous c.2810C-G transversion in exon 6 of the ZNF687 gene, resulting in a pro937-to-arg (P937R) substitution at a highly conserved residue in the nuclear localization signal. Patients carrying the mutation had a high prevalence (up to 30%) of the development of giant cell tumors. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, fell within a linked candidate region and segregated with the disorder in the family. It was filtered against the dbSNP (build 131) database and 4 in-house exome databases, and was not found in 564 unrelated control individuals from the same geographic region. The same heterozygous mutation was subsequently found in 7 unrelated patients with PDB complicated by giant cell tumors; most of the patients were of Italian descent. Haplotype analysis suggested a founder effect common to most of the patients. Subsequent cohort studies identified the P937R mutation in 1 of 30 families with PDB and in 5 additional patients with PDB. Patient cells showed higher levels of the protein in the nucleus and less in the cytoplasm compared to controls, suggesting that the mutation leads to enhanced availability of this transcription factor in the nucleus, resulting in a gain of function. ZNF687 expression was increased in patient peripheral blood cells compared to controls, as well as in patient tumor tissue. Patient osteoclasts showed a greater number of nuclei and a larger surface area compared to controls, consistent with Paget disease. (less)
|
Comment:
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a likely mechanism of disease in this gene and is associated with Paget disease of bone 6 (MIM#616833). Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID: 26849110). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - Variant is heterozygous. (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 50 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v3: 66 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated nuclear localization signal (PMID: 29493781). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg937His) variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the Italian population and has been suggested to be a founder mutation (ClinVar, PMID: 26849110, 29493781). (SP) 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:
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 937 of the ZNF687 protein (p.Pro937Arg). This variant is present in population databases (rs148402804, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Paget disease (PMID: 26849110, 29493781). ClinVar contains an entry for this variant (Variation ID: 222987). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a likely mechanism of disease in this gene and is associated with Paget disease of bone 6 (MIM#616833). Gain of function has specifically been demonstrated for the p.(Pro987Arg) variant (PMID: 26849110). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (I) 0251 - Variant is heterozygous. (I) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 50 heterozygotes, 0 homozygotes). (I) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (v3: 66 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated nuclear localization signal (PMID: 29493781). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg937His) variant has been classified as a VUS by clinical diagnostic laboratories (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is well-reported in the Italian population and has been suggested to be a founder mutation (ClinVar, PMID: 26849110, 29493781). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| ZNF687 mutations are frequently found in pagetic patients from South Italy: implication in the pathogenesis of Paget's disease of bone. | Divisato G | Clinical genetics | 2018 | PMID: 29493781 |
| ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor. | Divisato G | American journal of human genetics | 2016 | PMID: 26849110 |
| Giant cell tumor occurring in familial Paget's disease of bone: report of clinical characteristics and linkage analysis of a large pedigree. | Gianfrancesco F | Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research | 2013 | PMID: 22936311 |
| Giant cell tumor and Paget's disease of bone in one family: geographic clustering. | Rendina D | Clinical orthopaedics and related research | 2004 | PMID: 15123951 |
Text-mined citations for rs148402804 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.