ClinVar Miner

Submissions for variant NM_138413.4(HOGA1):c.700+5G>T (rs185803104)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000186492 SCV000485685 pathogenic Primary hyperoxaluria, type III 2016-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000520586 SCV000617211 pathogenic not provided 2015-11-23 criteria provided, single submitter clinical testing The c.700+5G>T pathogenic variant in the HOGA1 gene has been reported in association with primary hyperoxaluria, and has been proposed as a founder mutation in the central European population (Belostotsky et al., 2010; Monico et al., 2011; Williams et al., 2012; Beck et al., 2013). This variant reduces the quality of the splice donor site in intron 5, and is expected to cause abnormal gene splicing. While not found in the NHLBI Exome Sequencing Project in the homozygous state, the c.700+5G>T variant was observed in 26/8600 alleles (0.30%) from individuals of European ancestry. We interpret c.700+5G>T as a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000186492 SCV000711965 pathogenic Primary hyperoxaluria, type III 2016-04-05 criteria provided, single submitter clinical testing 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.
Fulgent Genetics,Fulgent Genetics RCV000186492 SCV000893163 pathogenic Primary hyperoxaluria, type III 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000186492 SCV000915486 pathogenic Primary hyperoxaluria, type III 2018-12-07 criteria provided, single submitter clinical testing 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.
Invitae RCV000520586 SCV000931941 pathogenic not provided 2019-01-06 criteria provided, single submitter clinical testing 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs185803104, ExAC 0.2%). This variant has been observed in the homozygous and compound heterozygous state in a large number of individuals affected with HOGA1-related primary hyperoxaluria type 3 (PMID: 24563386, 22781098, 22391140, 25644115). ClinVar contains an entry for this variant (Variation ID: 204285). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this intronic change leads to a splicing defect which has a deleterious effect on protein function (PMID: 21896830, 27096395, 22781098). For these reasons, this variant has been classified as Pathogenic.
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000186492 SCV000239854 pathogenic Primary hyperoxaluria, type III 2014-11-27 no assertion criteria provided research Abnormally spliced hepatic RNA (PMID:22391140)
GeneReviews RCV000186492 SCV000246175 pathogenic Primary hyperoxaluria, type III 2015-07-09 no assertion criteria provided literature only

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