Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant has been reported to be associated with HOGA1 related disorder (ClinVar ID: VCV000204269 / PMID: 22391140). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_138413.4(HOGA1):c.208C>T (p.Arg70Ter)
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.
(10)
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.
Pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_138413.4(HOGA1):c.208C>T (p.Arg70Ter)
Variation ID: 204269 Accession: VCV000204269.23
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q24.2 10: 97584911 (GRCh38) [ NCBI UCSC ] 10: 99344668 (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 21, 2015 Oct 26, 2024 Sep 5, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_138413.4:c.208C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_612422.2:p.Arg70Ter nonsense NM_001134670.2:c.208C>T NP_001128142.1:p.Arg70Ter nonsense NC_000010.11:g.97584911C>T NC_000010.10:g.99344668C>T NG_027922.1:g.5567C>T NG_034079.1:g.17471C>T - Protein change
- R70*
- Other names
- -
- Canonical SPDI
- NC_000010.11:97584910:C:T
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
- 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. |
|||
| HOGA1 | - | - |
GRCh38 GRCh37 |
493 | 519 | |
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. |
|---|---|---|---|---|
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Sep 5, 2024 | RCV000186476.21 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 5, 2023 | RCV000795411.7 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Apr 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790723.1
First in ClinVar: Jul 21, 2015 Last updated: Jul 21, 2015 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893856.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002520944.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant has been reported to be associated with HOGA1 related disorder (ClinVar ID: VCV000204269 / PMID: 22391140). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Steroid-resistant nephrotic syndrome (present) , Nephrolithiasis (present)
|
|
|
Pathogenic
(Oct 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: yes
Allele origin:
germline
|
Clinical Biochemistry Laboratory, Health Services Laboratory
Accession: SCV000239835.2
First in ClinVar: Jul 21, 2015 Last updated: Dec 09, 2023 |
Comment:
ACMG: PVS1 PM2 PM3
|
|
|
Pathogenic
(Nov 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000934874.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg70*) in the HOGA1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg70*) in the HOGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HOGA1 are known to be pathogenic (PMID: 22391140, 22781098). This variant is present in population databases (rs758304537, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria type 3 (PMID: 22391140, 25629080, 27742850). ClinVar contains an entry for this variant (Variation ID: 204269). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Sep 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV000914473.2
First in ClinVar: May 27, 2019 Last updated: Oct 13, 2024 |
|
|
|
Pathogenic
(Jan 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171970.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
Comment:
The missense c.208C>T (p.Arg70Ter) variant in HOGA1 gene has been reported previously in compound heterozygous state in individuals affected with primary hyperoxaluria type III (Williams … (more)
The missense c.208C>T (p.Arg70Ter) variant in HOGA1 gene has been reported previously in compound heterozygous state in individuals affected with primary hyperoxaluria type III (Williams et al. 2012; Williams et al. 2015; Richard et al. 2017). The c.208C>T variant is reported with an allele frequency of 0.004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathognic (multiple submissions). The nucleotide change c.208C>T in HOGA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV005380818.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
Variant summary: HOGA1 c.208C>T (p.Arg70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: HOGA1 c.208C>T (p.Arg70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 248150 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (4e-05 vs 0.0015), allowing no conclusion about variant significance. c.208C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (e.g. Martin-Higueras_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33865885). ClinVar contains an entry for this variant (Variation ID: 204269). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Sep 10, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type III
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002094526.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Aug 26, 2024)
|
no assertion criteria provided
Method: clinical testing
|
Primary hyperoxaluria type 3
Affected status: yes
Allele origin:
paternal
|
Chinese Inherited Urolithiasis Consortium, The Affiliated Yantai Yuhuangding Hospital of Qingdao University
Accession: SCV005368628.1
First in ClinVar: Oct 13, 2024 Last updated: Oct 13, 2024 |
Comment:
Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Nonconserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs758304537
Number of individuals with the variant: 1
Sex: male
Ethnicity/Population group: Asian
Geographic origin: China
|
Comment:
Comment:
ACMG: PVS1 PM2 PM3
Comment:
This sequence change creates a premature translational stop signal (p.Arg70*) in the HOGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HOGA1 are known to be pathogenic (PMID: 22391140, 22781098). This variant is present in population databases (rs758304537, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria type 3 (PMID: 22391140, 25629080, 27742850). ClinVar contains an entry for this variant (Variation ID: 204269). For these reasons, this variant has been classified as Pathogenic.
Comment:
The missense c.208C>T (p.Arg70Ter) variant in HOGA1 gene has been reported previously in compound heterozygous state in individuals affected with primary hyperoxaluria type III (Williams et al. 2012; Williams et al. 2015; Richard et al. 2017). The c.208C>T variant is reported with an allele frequency of 0.004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathognic (multiple submissions). The nucleotide change c.208C>T in HOGA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: HOGA1 c.208C>T (p.Arg70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 248150 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (4e-05 vs 0.0015), allowing no conclusion about variant significance. c.208C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (e.g. Martin-Higueras_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33865885). ClinVar contains an entry for this variant (Variation ID: 204269). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Nonconserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs758304537
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:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant has been reported to be associated with HOGA1 related disorder (ClinVar ID: VCV000204269 / PMID: 22391140). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
ACMG: PVS1 PM2 PM3
Comment:
This sequence change creates a premature translational stop signal (p.Arg70*) in the HOGA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HOGA1 are known to be pathogenic (PMID: 22391140, 22781098). This variant is present in population databases (rs758304537, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with primary hyperoxaluria type 3 (PMID: 22391140, 25629080, 27742850). ClinVar contains an entry for this variant (Variation ID: 204269). For these reasons, this variant has been classified as Pathogenic.
Comment:
The missense c.208C>T (p.Arg70Ter) variant in HOGA1 gene has been reported previously in compound heterozygous state in individuals affected with primary hyperoxaluria type III (Williams et al. 2012; Williams et al. 2015; Richard et al. 2017). The c.208C>T variant is reported with an allele frequency of 0.004% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance / Pathognic (multiple submissions). The nucleotide change c.208C>T in HOGA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: HOGA1 c.208C>T (p.Arg70X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-05 in 248150 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (4e-05 vs 0.0015), allowing no conclusion about variant significance. c.208C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (e.g. Martin-Higueras_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33865885). ClinVar contains an entry for this variant (Variation ID: 204269). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Variant_type:missense/MutationTaster:Disease_causing_automatic/CADD:Damaging/phyloP:Nonconserved/phastCons:Conserved/gnomAD_exome_EastAsian:0/ExAC_EastAsian:0/dbSNP:rs758304537
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A report from the European Hyperoxaluria Consortium (OxalEurope) Registry on a large cohort of patients with primary hyperoxaluria type 3. | Martin-Higueras C | Kidney international | 2021 | PMID: 33865885 |
| Nine novel HOGA1 gene mutations identified in primary hyperoxaluria type 3 and distinct clinical and biochemical characteristics in Chinese children. | Fang X | Pediatric nephrology (Berlin, Germany) | 2019 | PMID: 31123811 |
| Identification of 8 novel gene variants in primary hyperoxaluria in 21 Chinese children with urinary stones. | He L | World journal of urology | 2019 | PMID: 30488096 |
| Late diagnosis of primary hyperoxaluria type III. | Richard E | Annals of clinical biochemistry | 2017 | PMID: 27742850 |
| Renal function can be impaired in children with primary hyperoxaluria type 3. | Allard L | Pediatric nephrology (Berlin, Germany) | 2015 | PMID: 25972204 |
| 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 |
| 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 3. | Williams EL | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2012 | PMID: 22391140 |
Text-mined citations for rs758304537 ...
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 Oct 27, 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.