ClinVar Genomic variation as it relates to human health
NM_138413.4(HOGA1):c.700+5G>T
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_138413.4(HOGA1):c.700+5G>T
Variation ID: 204285 Accession: VCV000204285.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q24.2 10: 97600168 (GRCh38) [ NCBI UCSC ] 10: 99359925 (GRCh37) [ 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 Jul 21, 2015 Mar 16, 2024 Jan 28, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_138413.4:c.700+5G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001134670.2:c.212-1689G>T intron variant NC_000010.11:g.97600168G>T NC_000010.10:g.99359925G>T NG_027922.1:g.20824G>T - Protein change
- Other names
- missplicing
- Canonical SPDI
- NC_000010.11:97600167:G:T
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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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0.00060 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00060
1000 Genomes Project 30x 0.00078
Exome Aggregation Consortium (ExAC) 0.00111
The Genome Aggregation Database (gnomAD), exomes 0.00124
The Genome Aggregation Database (gnomAD) 0.00156
Trans-Omics for Precision Medicine (TOPMed) 0.00159
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00215
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 | ||
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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
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. |
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HOGA1 | - | - |
GRCh38 GRCh37 |
482 | 508 |
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. |
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Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
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Jun 28, 2022 | RCV000186492.21 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2024 | RCV000520586.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 5, 2023 | RCV003937657.1 |
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. |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893163.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Dec 07, 2018)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000915486.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The HOGA1 c.700+5G>T splice_region variant has been reported in at least six studies in which it is found in at least 36 patients with primary … (more)
The HOGA1 c.700+5G>T splice_region variant has been reported in at least six studies in which it is found in at least 36 patients with primary hyperoxaluria, including in 24 in a homozygous state and in 12 in a compound heterozygous state (Belostotsky et al. 2010; Monico et al. 2011; Williams et al. 2012; Beck et al. 2013; Hopp et al. 2015). This variant is described as the most common pathogenic variant in the HOGA1 gene, being identified in 67% of disease alleles (Hoppe et al. 2012). The c.700+5G>T variant was absent from 113 controls, but is reported at a frequency of 0.00302 in the European American population of the Exome Aggregation Consortium. Williams et al. (2012) utilized RNA from a patient who was homozygous for the c.700+5G>T variant to demonstrate that there was activation of a cryptic splice site via an inframe insertion of 51 nucleotides and 17 amino acids. Based on the collective evidence, the c.700+5G>T variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Apr 05, 2016)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria, type III
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711965.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Comment:
The c.700+5G>T variant in HOGA1 is one of the most common HOGA1 pathogenic varia nts in patients with primary hyperoxaluria type 3 (Belostosky 2010, Williams … (more)
The c.700+5G>T variant in HOGA1 is one of the most common HOGA1 pathogenic varia nts in patients with primary hyperoxaluria type 3 (Belostosky 2010, Williams 201 2). This variant has been identified in 0.2% (247/126672) of European chromosome s by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs185803104). Although this variant has been seen in the general populati on, its frequency is low enough to be consistent with a recessive carrier freque ncy. This variant is located in the 5' splice region and was demonstrated to lea d to altered splicing and in-frame insertion of 52 nucleotides in patient cells (Monico 2011, Williams 2012). In summary, this variant meets our criteria to be classified as pathogenic for primary hyperoxaluria type 3 in an autosomal recess ive manner. ACMG/AMP Criteria applied: PM3_VeryStrong; PM2; PM4. (less)
Number of individuals with the variant: 5
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Pathogenic
(Dec 17, 2019)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194117.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_138413.3(HOGA1):c.700+5G>T is classified as pathogenic in the context of primary hyperoxaluria type 3. Sources cited for classification include the following: PMID 22781098, 22391140, 21896830 and … (more)
NM_138413.3(HOGA1):c.700+5G>T is classified as pathogenic in the context of primary hyperoxaluria type 3. Sources cited for classification include the following: PMID 22781098, 22391140, 21896830 and 20797690. Classification of NM_138413.3(HOGA1):c.700+5G>T is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
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Pathogenic
(Apr 23, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714359.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS4, PS3, PP4
Number of individuals with the variant: 1
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Pathogenic
(Jun 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556221.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: HOGA1 c.700+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly … (more)
Variant summary: HOGA1 c.700+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Indeed, it has been demonstrated that the variant weakens the wild-type 5' donor splice site resulting instead in the activation of a downstream cryptic splice site which produces an in-frame insertion of 51 nucleotides (17 codons) from intron 5 (e.g. Monico_2011, Williams_2012).The variant allele was found at a frequency of 0.0012 in 251412 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (0.0012 vs 0.0015). c.700+5G>T has been reported in the literature in many homozygous and compound heterozygous individuals affected with Primary Hyperoxaluria, Type III, predominantly of European ancestry (e.g. Belostotsky_2010, Monico_2011, Williams_2012, Beck_2013, Williams_2015). It is described as a common pathogenic variant in HOGA1, having been reported at allele frequencies of 47-67% in patients with Primary Hyperoxaluria, Type III and it has been suggeted that it represents a founder variant in the northern European population (Williams_2012, Beck_2013). These data indicate that the variant is very likely to be associated with disease. Ten assessments for this variant have been submitted to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Primary hyperoxaluria type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768236.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with primary hyperoxaluria type III (MIM#613616). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity with regard to phenotype severity and age of onset (PMID: 25644115). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant has been shown by RNA studies to result in the use of a cryptic splice site, predicted to result in the in-frame insertion of 17 amino acids (PMID: 21896830, 22391140). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (335 heterozygotes, 1 homozygote). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is the most common primary hyperoxaluria type III-associated variant in European populations (ClinVar; PMID: 21896830, 22391140, 25644115). (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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Pathogenic
(Feb 17, 2021)
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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: SCV000617211.4
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate the variant results in an in-frame insertion of 51bp due to weakening of the natural splice site and use of a … (more)
Published functional studies demonstrate the variant results in an in-frame insertion of 51bp due to weakening of the natural splice site and use of a downstream cryptic splice site (Monico et al., 2011; Williams et al., 2012; Beck et al., 2013); In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22391140, 25644115, 30609409, 21896830, 24563386, 20797690, 22781098, 27096395, 26401545, 22851625, 26340091, 25629080, 25972204, 28711958, 27838384, 31980526, 34426522, 31589614, 33226606) (less)
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Pathogenic
(Nov 17, 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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Revvity Omics, Revvity
Accession: SCV002025008.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 28, 2024)
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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: SCV000931941.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 5 of the HOGA1 gene. It does not directly change the encoded amino acid sequence of the HOGA1 protein. … (more)
This sequence change falls in intron 5 of the HOGA1 gene. It does not directly change the encoded amino acid sequence of the HOGA1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 17 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs185803104, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with HOGA1-related primary hyperoxaluria type 3 (PMID: 22391140, 22781098, 24563386, 25644115). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 204285). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the activation of a cryptic splice site in intron 5 (PMID: 21896830). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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HOGA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004750388.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The HOGA1 c.700+5G>T variant is predicted to interfere with splicing. This variant has been reported to be pathogenic for primary hyperoxaluria (Hopp et al. 2015. … (more)
The HOGA1 c.700+5G>T variant is predicted to interfere with splicing. This variant has been reported to be pathogenic for primary hyperoxaluria (Hopp et al. 2015. PubMed ID: 25644115; Beck et al. 2013. PubMed ID: 22781098; reported as c.701+4G>T in Belostotsky et al. 2010. PubMed ID: 20797690). This variant is reported in 0.20% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, this variant is interpreted as pathogenic. (less)
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Pathogenic
(Nov 27, 2014)
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no assertion criteria provided
Method: research
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Primary hyperoxaluria, type III
Affected status: yes
Allele origin:
germline
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Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV000239854.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
Comment:
Abnormally spliced hepatic RNA (PMID:22391140)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Primary hyperoxaluria type III
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001455549.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Primary hyperoxaluria type 3
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000246175.2
First in ClinVar: Sep 29, 2015 Last updated: Oct 01, 2022 |
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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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Primary Hyperoxaluria Type 3. | Adam MP | - | 2023 | PMID: 26401545 |
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. | Ceyhan-Birsoy O | American journal of human genetics | 2019 | PMID: 30609409 |
Cellular degradation of 4-hydroxy-2-oxoglutarate aldolase leads to absolute deficiency in primary hyperoxaluria type 3. | MacDonald JR | FEBS letters | 2016 | PMID: 27096395 |
Phenotype-Genotype Correlations and Estimated Carrier Frequencies of Primary Hyperoxaluria. | Hopp K | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25644115 |
Performance evaluation of Sanger sequencing for the diagnosis of primary hyperoxaluria and comparison with targeted next generation sequencing. | Williams EL | Molecular genetics & genomic medicine | 2015 | PMID: 25629080 |
4-hydroxyglutamate is a biomarker for primary hyperoxaluria type 3. | Pitt JJ | JIMD reports | 2015 | PMID: 24563386 |
Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies. | Beck BB | European journal of human genetics : EJHG | 2013 | PMID: 22781098 |
The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type III. | Hoppe B | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2012 | PMID: 22851625 |
The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type 3. | Williams EL | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2012 | PMID: 22391140 |
Primary hyperoxaluria type III gene HOGA1 (formerly DHDPSL) as a possible risk factor for idiopathic calcium oxalate urolithiasis. | Monico CG | Clinical journal of the American Society of Nephrology : CJASN | 2011 | PMID: 21896830 |
Mutations in DHDPSL are responsible for primary hyperoxaluria type III. | Belostotsky R | American journal of human genetics | 2010 | PMID: 20797690 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
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Text-mined citations for rs185803104 ...
HelpRecord last updated Mar 17, 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.