Submissions for variant NM_138413.4(HOGA1):c.107C>T (p.Ala36Val)

gnomAD frequency: 0.00016  dbSNP: rs201803986

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186472	SCV000239830	pathogenic	Primary hyperoxaluria type 3	2023-10-27	criteria provided, single submitter	clinical testing	Biochemical confirmation. ACMG: PS3 PM2 PM3 PP4
Illumina Laboratory Services, Illumina	RCV000186472	SCV000366314	likely pathogenic	Primary hyperoxaluria type 3	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001060485	SCV001225177	pathogenic	not provided	2024-04-02	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 36 of the HOGA1 protein (p.Ala36Val). This variant is present in population databases (rs201803986, gnomAD 0.3%). This missense change has been observed in individual(s) with HOGA1-related conditions (PMID: 22391140, 24563386; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 204265). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HOGA1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000186472	SCV001821215	likely pathogenic	Primary hyperoxaluria type 3	2023-05-30	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 significantly higher than estimated for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (0.00017 vs 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 (examples: 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). The following publications have been ascertained in the context of this evaluation (PMID: 33350326, 31589614, 24563386, 25629080, 22391140). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) or likely pathogenic/pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV000186472	SCV002060312	uncertain significance	Primary hyperoxaluria type 3	2022-01-04	criteria provided, single submitter	clinical testing	NM_138413.3(HOGA1):c.107C>T(A36V) is a missense variant classified as a variant of uncertain significance in the context of primary hyperoxaluria type 3. A36V has been observed in cases with relevant disease (PMID: 22391140, 24563386, 33350326). Functional assessments of this variant are not available in the literature. A36V has been observed in population frequency databases (gnomAD: ASJ 0.29%). In summary, there is insufficient evidence to classify NM_138413.3(HOGA1):c.107C>T(A36V) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000186472	SCV005678486	likely pathogenic	Primary hyperoxaluria type 3	2024-01-29	criteria provided, single submitter	clinical testing