Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Clinical Services Laboratory, |
RCV000186472 | SCV000366314 | likely pathogenic | Primary hyperoxaluria, type III | 2017-04-27 | criteria provided, single submitter | clinical testing | The HOGA1 c.107C>T (p.Ala36Val) missense variant has been reported in three studies in which it is found in at least three patients with primary hyperoxaluria type III (PH3) in a compound heterozygous state and in a heterozygous state in one additional patient who also carried a heterozygous deletion in the AGXT gene, which is associated with PH1 (Williams et al. 2012; Pitt et al. 2014; Williams et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of levels of the metabolic precursor of the HOGA1 substrate revealed that PH3 patients had significantly higher levels compared to age-matched controls, and that parental carriers showed moderate but significant increases in levels (Pitt et al. 2014). Based on the evidence, the p.Ala36Val variant is classified as likely pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV001060485 | SCV001225177 | uncertain significance | not provided | 2019-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine with valine at codon 36 of the HOGA1 protein (p.Ala36Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201803986, ExAC 0.02%). This variant has been observed in several individuals with HOGA1-related conditions (PMID: 22391140, 24563386). ClinVar contains an entry for this variant (Variation ID: 204265). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000186472 | SCV001821215 | likely pathogenic | Primary hyperoxaluria, type III | 2021-08-10 | criteria provided, single submitter | clinical testing | Variant summary: HOGA1 c.107C>T (p.Ala36Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 249960 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (0.0015), allowing no conclusion about variant significance. c.107C>T has been reported in the literature in multiple compound heterozygous individuals affected with Primary Hyperoxaluria, Type III (Williams_2012, Williams_2015, Pitt_2015, Bar_2021). These data indicate that the variant is likely to be associated with disease. One publication reported that the excretion of 4-Hydroxyglutamate (the metabolic precursor of the HOGA1 substrate) was elevated in Primary Hyperoxaluria, Type III patients; this cohort included at least one of the reported affected individuals who was carrying the variant of interest, though no patient specific data were provided (Pitt_2015). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Clinical Biochemistry Laboratory, |
RCV000186472 | SCV000239830 | pathogenic | Primary hyperoxaluria, type III | 2014-11-27 | no assertion criteria provided | in vitro | Predicted benign but found in trans with c.700+5G>T and c.944_946del. Also found by Pitt et al., 2014 (PMID:24563386). |
| Counsyl | RCV000186472 | SCV001132225 | uncertain significance | Primary hyperoxaluria, type III | 2018-03-20 | no assertion criteria provided | clinical testing |