NM_138413.4(HOGA1):c.700+5G>T AND Primary hyperoxaluria type 3

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Jun 28, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000186492.21

Allele description

NM_138413.4(HOGA1):c.700+5G>T

Gene:

HOGA1:4-hydroxy-2-oxoglutarate aldolase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q24.2

Genomic location:

Preferred name:

NM_138413.4(HOGA1):c.700+5G>T

Other names:

missplicing

HGVS:

NC_000010.11:g.97600168G>T
NG_027922.1:g.20824G>T
NM_001134670.2:c.212-1689G>T
NM_138413.4:c.700+5G>TMANE SELECT
NC_000010.10:g.99359925G>T
NM_138413.3:c.700+5G>T

Links:

dbSNP: rs185803104

NCBI 1000 Genomes Browser:

rs185803104

Molecular consequence:

NM_001134670.2:c.212-1689G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_138413.4:c.700+5G>T - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Primary hyperoxaluria type 3
Synonyms:: PH III; Primary hyperoxaluria, type III
Identifiers:: MONDO: MONDO:0013327; MedGen: C3150878; Orphanet: 416; Orphanet: 93600; OMIM: 613616

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000239854	Clinical Biochemistry Laboratory, Health Services Laboratory	no assertion criteria provided	Pathogenic (Nov 27, 2014)	germline	research	PubMed (3) [See all records that cite these PMIDs] 20797690, 22391140, 22781098
SCV000246175	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000711965	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Apr 5, 2016)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22391140, 21896830, 20797690, 24033266
SCV000893163	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000915486	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Dec 7, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21896830, 22781098, 20797690, 22851625, 25644115, 22391140 Citation Link,
SCV001194117	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 17, 2019)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 22781098, 22391140, 21896830, 20797690 Citation Link,
SCV001455549	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002556221	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 28, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25629080, 22391140, 22781098, 21896830, 20797690 Citation Link,
SCV002768236	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21896830, 22391140, 25644115, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	5	5	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only, research

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

The enzyme 4-hydroxy-2-oxoglutarate aldolase is deficient in primary hyperoxaluria type III.

Hoppe B.

Nephrol Dial Transplant. 2012 Aug;27(8):3024-6. doi: 10.1093/ndt/gfs308. No abstract available.

PubMed [citation]

PMID:: 22851625

See all PubMed Citations (9)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Clinical Biochemistry Laboratory, Health Services Laboratory, SCV000239854.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (3)

Description

Abnormally spliced hepatic RNA (PMID:22391140)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000246175.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000711965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		5	not provided	5	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893163.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000915486.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194117.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001455549.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002556221.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002768236.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Mar 16, 2024

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