ClinVar Miner

Submissions for variant NM_138413.4(HOGA1):c.938_940AGG[2] (p.Glu315del) (rs397509360)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000000046 SCV000245619 pathogenic Primary hyperoxaluria, type III 2018-09-07 criteria provided, single submitter clinical testing The p.Glu315del variant in HOGA1 is an established pathogenic variant associated with primary hyperoxaluria type III. It is one of the two most commonly observe d pathogenic variants in HOGA1 and has been identified in the homozygous or comp ound heterozygous state in multiple affected individuals and segregated with dis ease in multiple affected family members (Belostotsky 2010, Monico 2011, William s 2012, Hopp 2015). It is prevalent in the Ashkenazi Jewish population and has b een identified in 0.9% of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad. broadinstitute.org). In vitro functional studies suggest that this variant impac ts protein function (MacDonald 2016). In summary, this variant meets our criteri a to be classified as pathogenic for primary hyperoxaluria type III in an autoso mal recessive manner. ACMG/AMP Criteria applied: PP1_Very Strong, PS3_Moderate. PM4_Supporting.
Counsyl RCV000000046 SCV000678132 pathogenic Primary hyperoxaluria, type III 2017-01-25 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000000046 SCV000915489 pathogenic Primary hyperoxaluria, type III 2018-10-19 criteria provided, single submitter clinical testing The HOGA1 c.944_946delAGG (p.Glu315del) variant results in an inframe deletion. Across a selection of the available literature, the p.Glu315del variant has been identified in a total of 38 individuals with primary hyperoxaluria including 15 homozygotes and 23 compound heterozygotes (Belostotsky et al. 2010; Monico et al. 2011; Williams et al. 2012; Hopp et al. 2015; Pitt et al. 2015; Williams et al. 2015). The second variant carried by the compound heterozygotes is either a missense or splice_region variant. The p.Glu315del variant was absent from 113 controls and is reported at a frequency of 0.008967 in the Ashkenazi Jewish population of the Genome Aggregation Database. Expression of the p.Glu315del variant protein in CHO cells revealed that the protein was mislocalized and retained no measurable activity (Riedel et al. 2012). Expression analysis in HEK293 cells demonstrated the p.Glu315del variant protein was unstable and was only detected in the presence of 26S proteasome inhibitor (MacDonald et al. 2016). Based on the collective evidence, the p.Glu315del 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 RCV000815800 SCV000956272 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This variant, c.944_946delAGG, results in the deletion of 1 amino acid of the HOGA1 protein (p.Glu315del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758714937, ExAC 0.07%). This variant is a common cause of hyperoxaluria in the Ashkenazi Jew population (PMID: 20797690). ClinVar contains an entry for this variant (Variation ID: 29). Experimental studies have shown that this missense change leads to HOGA1 protein instability (PMID: 22771891, 27096395). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000046 SCV000020189 pathogenic Primary hyperoxaluria, type III 2010-09-10 no assertion criteria provided literature only
Clinical Biochemistry Laboratory,Health Services Laboratory RCV000000046 SCV000239858 pathogenic Primary hyperoxaluria, type III 2014-11-27 no assertion criteria provided research Prevalent in Jewish-Ashkenazi
GeneReviews RCV000000046 SCV000246174 pathogenic Primary hyperoxaluria, type III 2015-07-09 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000000046 SCV001142411 pathogenic Primary hyperoxaluria, type III 2020-01-06 no assertion criteria provided curation NM_138413.3:c.944_946delAGG in the HOGA1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. Belostotsky et al. reported that three independent families harboring homozygous for this variant, leading to the loss of one glutamic acid residue (PMID: 20797690). In addition, Monico et al. reported mutiple patients are compound heterozygous with another pathogenic variant and segregated (PMID: 21896830). Experimental studies have shown that this missense change leads to HOGA1 protein instability (PMID: 22771891; 27096395). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3.

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