ClinVar Genomic variation as it relates to human health
NM_000860.6(HPGD):c.310_311del (p.Leu104fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000860.6(HPGD):c.310_311del (p.Leu104fs)
Variation ID: 156027 Accession: VCV000156027.10
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 4q34.1 4: 175439135-175439136 (GRCh37) [ NCBI UCSC ] 4: 174517984-174517985 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 17, 2016 Feb 14, 2024 Oct 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000860.6:c.310_311del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000851.2:p.Leu104fs frameshift NM_000860.5:c.310_311delCT NM_001145816.3:c.310_311del NP_001139288.1:p.Leu104fs frameshift NM_001256301.1:c.-56CT[1] 5 prime UTR NM_001256305.2:c.310_311del NP_001243234.1:p.Leu104fs frameshift NM_001256306.2:c.217+3959_217+3960del intron variant NM_001256307.2:c.-40+3959_-40+3960del intron variant NM_001363574.2:c.310_311del NP_001350503.1:p.Leu104fs frameshift NC_000004.12:g.174517984AG[1] NC_000004.11:g.175439135AG[1] NG_011689.1:g.9655CT[1] - Protein change
- L104fs
- Other names
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- Canonical SPDI
- NC_000004.12:174517983:AGAG:AG
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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HPGD | - | - |
GRCh38 GRCh37 |
172 | 243 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
no assertion criteria provided
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May 12, 2014 | RCV000144086.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 22, 2018 | RCV000779438.5 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 25, 2023 | RCV002222407.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 21, 2023 | RCV003398781.4 |
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
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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
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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
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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. |
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Pathogenic
(Aug 22, 2018)
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criteria provided, single submitter
Method: clinical testing
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HPGD-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000916054.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The HPGD c.310_311delCT (p.Leu104AlafsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu104AlafsTer3 variant has been … (more)
The HPGD c.310_311delCT (p.Leu104AlafsTer3) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Leu104AlafsTer3 variant has been identified in 13 individuals with primary hypertrophic osteoarthropathy, including in a homozygous state in ten probands, in a compound heterozygous state in one proband, and in a heterozygous state in two probands in whom a second variant was not identified (Tüysüz et al. 2014; Erken et al. 2015; Yuan et al. 2015). The p.Leu104AlafsTer3 variant was also found in a heterozygous state in nine unaffected relatives of the probands. The p.Leu104AlafsTer3 variant was absent from 236 controls and is reported at a frequency of 0.00061 in the East Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Leu104AlafsTer3 is classified as pathogenic for HPGD-related disorders. (less)
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Pathogenic
(Apr 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002499790.2
First in ClinVar: Apr 23, 2022 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 29652982, 25863089, 28253600, 30215240, 30292630, 24816859, 24533558, 31063976) (less)
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Pathogenic
(Apr 21, 2023)
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criteria provided, single submitter
Method: clinical testing
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HPGD-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004104747.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The HPGD c.310_311delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu104Alafs*3). This variant has been reported in multiple individuals with … (more)
The HPGD c.310_311delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu104Alafs*3). This variant has been reported in multiple individuals with primary hypertrophic osteoarthropathy in the homozygous or compound heterozygous state (see for example, Erken et al 2015. PubMed ID: 24533558; Tüysüz B et al 2014. PubMed ID: 24816859; Lu et al. 2022. PubMed ID: 35813463). This variant is reported in 0.060% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-175439134-CAG-C). Frameshift variants in HPGD are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003525618.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Leu104Alafs*3) in the HPGD gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Leu104Alafs*3) in the HPGD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HPGD are known to be pathogenic (PMID: 18500342, 19568269, 24533558, 24816859). This variant is present in population databases (rs587777719, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with primary hypertrophic osteoarthropathy (PMID: 24533558). ClinVar contains an entry for this variant (Variation ID: 156027). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Hypertrophic osteoarthropathy, primary, autosomal recessive, 1
Affected status: yes
Allele origin:
germline
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Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Accession: SCV000484925.1
First in ClinVar: Dec 17, 2016 Last updated: Dec 17, 2016 |
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Pathogenic
(Feb 18, 2014)
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no assertion criteria provided
Method: literature only
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HYPERTROPHIC OSTEOARTHROPATHY, PRIMARY, AUTOSOMAL RECESSIVE, 1
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000189161.3
First in ClinVar: Sep 22, 2014 Last updated: Oct 08, 2017 |
Comment on evidence:
In a sister and brother with primary hypertrophic osteoarthropathy (PHOAR1; 259100) from a consanguineous Turkish family, Erken et al. (2015) identified homozygosity for a 2-bp … (more)
In a sister and brother with primary hypertrophic osteoarthropathy (PHOAR1; 259100) from a consanguineous Turkish family, Erken et al. (2015) identified homozygosity for a 2-bp deletion (c.310_311delCT) in exon 3 of the HPGD gene, causing a frameshift predicted to result in a premature termination codon (Leu104AlafsTer3). The unaffected parents and 5 other unaffected family members were heterozygous for the mutation; examination revealed no signs of the disease in the heterozygous carriers. The mutation was not found in 136 Turkish controls, showing with at least 80% probability that the deletion was not a common variant in the Turkish population. (less)
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Pathogenic
(May 12, 2014)
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no assertion criteria provided
Method: literature only
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Hypertrophic osteoarthropathy, primary, autosomal recessive, 1
Affected status: yes
Allele origin:
germline
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Yale Center for Mendelian Genomics, Yale University
Accession: SCV000611564.1
First in ClinVar: Oct 08, 2017 Last updated: Oct 08, 2017 |
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Pathogenic
(-)
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no assertion criteria provided
Method: literature only
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Hypertrophic osteoarthropathy, primary, autosomal recessive, 1
Affected status: unknown
Allele origin:
de novo
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Prenatal Diagnosis Center, International Peace Maternity & Child Health Hospital
Accession: SCV004037447.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A Common Mutation and a Novel Mutation in the HPGD Gene in Nine Patients with Primary Hypertrophic Osteoarthropathy. | Yuan L | Calcified tissue international | 2015 | PMID: 26135126 |
A novel recessive 15-hydroxyprostaglandin dehydrogenase mutation in a family with primary hypertrophic osteoarthropathy. | Erken E | Modern rheumatology | 2015 | PMID: 24533558 |
Primary hypertrophic osteoarthropathy caused by homozygous deletion in HPGD gene in a family: changing clinical and radiological findings with long-term follow-up. | Tüysüz B | Rheumatology international | 2014 | PMID: 24816859 |
HPGD mutations cause cranioosteoarthropathy but not autosomal dominant digital clubbing. | Seifert W | European journal of human genetics : EJHG | 2009 | PMID: 19568269 |
Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. | Uppal S | Nature genetics | 2008 | PMID: 18500342 |
Text-mined citations for rs587777719 ...
HelpRecord last updated Mar 11, 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.