rs202047589
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM5PP3_ModeratePP5_Very_Strong
The NM_138413.4(HOGA1):c.569C>T(p.Pro190Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000564 in 1,614,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P190A) has been classified as Likely pathogenic.
Frequency
Consequence
NM_138413.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HOGA1 | NM_138413.4 | c.569C>T | p.Pro190Leu | missense_variant | 4/7 | ENST00000370646.9 | |
HOGA1 | NM_001134670.2 | c.212-2077C>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HOGA1 | ENST00000370646.9 | c.569C>T | p.Pro190Leu | missense_variant | 4/7 | 1 | NM_138413.4 | P1 | |
HOGA1 | ENST00000370647.8 | c.212-2077C>T | intron_variant | 1 | |||||
HOGA1 | ENST00000465608.1 | n.1413C>T | non_coding_transcript_exon_variant | 3/3 | 2 | ||||
HOGA1 | ENST00000370642.4 | upstream_gene_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251466Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135900
GnomAD4 exome AF: 0.0000554 AC: 81AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44AN XY: 727234
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74324
ClinVar
Submissions by phenotype
Primary hyperoxaluria type 3 Pathogenic:5
Pathogenic, no assertion criteria provided | research | Clinical Biochemistry Laboratory, Health Services Laboratory | Nov 27, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 14, 2021 | Variant summary: HOGA1 c.569C>T (p.Pro190Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251866 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in HOGA1 causing Primary Hyperoxaluria, Type III (4.4e-05 vs 0.0015), allowing no conclusion about variant significance. c.569C>T has been reported in the literature in multiple individuals affected with Primary Hyperoxaluria, Type III (Monico_2011, Beck_2012, Martin-Higueras_2021). Additionally, this variant was found in three homozygous patients in one family and co-segregated with disease (Beck_2012). These data indicate that the variant is very likely to be associated with disease. Functional studies report experimental evidence evaluating an impact on protein function and this variant effect results in reducing expressed hHOGA protein level and hHOGA activity compared to wild-type in transfected cells (Riedel_2012, Beck_2012). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic and likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 21, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 29, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 190 of the HOGA1 protein (p.Pro190Leu). This variant is present in population databases (rs202047589, gnomAD 0.04%). This missense change has been observed in individuals with primary hyperoxaluria (PMID: 21896830, 22781098, 27561601). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 204273). 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%. Experimental studies have shown that this missense change affects HOGA1 function (PMID: 22771891). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 08, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at