Submissions for variant NM_138413.4(HOGA1):c.134C>T (p.Pro45Leu)

dbSNP: rs764396564

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Biochemistry Laboratory, Health Services Laboratory	RCV000186473	SCV000239831	pathogenic	Primary hyperoxaluria type 3	2023-10-27	criteria provided, single submitter	clinical testing	Biochemical confirmation - raised urine oxalate and dihydroxyglutarate. ACMG:PM1 PM2 PP3 PP4 PP5 BP1
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513970	SCV003446731	pathogenic	not provided	2024-03-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the HOGA1 protein (p.Pro45Leu). This variant is present in population databases (rs764396564, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of hyperoxaluria (PMID: 26342005; Invitae). ClinVar contains an entry for this variant (Variation ID: 204266). 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 expected to disrupt HOGA1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000186473	SCV004048199	likely pathogenic	Primary hyperoxaluria type 3	2023-07-22	criteria provided, single submitter	clinical testing	The missense variant c.134C>T p.Pro45Leu in the HOGA1 gene has been reported previously in an individual in homozygous/hemizygous state affected with primary hyperoxaluria Clifford-Mobley et al., 2016. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic. The amino acid Pro at position 45 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Damaging, SIFT - Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The amino acid change p.Pro45Leu in HOGA1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000186473	SCV005678488	likely pathogenic	Primary hyperoxaluria type 3	2024-06-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895222	SCV004709264	uncertain significance	HOGA1-related disorder	2024-01-08	no assertion criteria provided	clinical testing	The HOGA1 c.134C>T variant is predicted to result in the amino acid substitution p.Pro45Leu. This variant has been reported in four individuals with primary hyperoxaluria type III; However, a second causative variant was not identified in two of these individuals (Table 3, Clifford-Mobley et al. 2016. PubMed ID: 26342005; Tables 1, 2 and S1, Abid et al. 2022. PubMed ID: 36259736; Table 4, Saha et al. 2023. PubMed ID: 37464296). This variant is reported in 0.10% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Genetics laboratory, Department of Obstetrics & Gynae, Institute of Kidney Diseases & Research Centre Dr. H.L. Trivedi Institute Of Transplantation Sciences	RCV000186473	SCV005397943	pathogenic	Primary hyperoxaluria type 3	2024-03-12	no assertion criteria provided	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the HOGA1 protein (p.Pro45Leu). This variant is present in population databases (rs764396564, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of hyperoxaluria. ClinVar contains an entry for this variant (Variation ID: 204266). 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 expected to disrupt HOGA1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.