10-97584810-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP5 BP4

The NM_138413.4(HOGA1):c.107C>T(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: HOGA1 NM_138413.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1
• Conservation: PhyloP100: 2.67

Genes affected

HOGA1 (HGNC:25155): (4-hydroxy-2-oxoglutarate aldolase 1) The authors of PMID:20797690 cloned this gene while searching for genes in a region of chromosome 10 linked to primary hyperoxalurea type III. They noted that even though the encoded protein has been described as a mitochondrial dihydrodipicolinate synthase-like enzyme, it shares little homology with E. coli dihydrodipicolinate synthase (Dhdps), particularly in the putative substrate-binding region. Moreover, neither lysine biosynthesis nor sialic acid metabolism, for which Dhdps is responsible, occurs in vertebrate mitochondria. They propose that this gene encodes mitochondrial 4-hydroxyl-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. This gene is predominantly expressed in the liver and kidney, and mutations in this gene are found in patients with primary hyperoxalurea type III. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_138413.4
• PP5: Variant 10-97584810-C-T is Pathogenic according to our data. Variant chr10-97584810-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204265.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.026173383).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOGA1	NM_138413.4	c.107C>T	p.Ala36Val	missense_variant	1/7	ENST00000370646.9
HOGA1	NM_001134670.2	c.107C>T	p.Ala36Val	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOGA1	ENST00000370646.9	c.107C>T	p.Ala36Val	missense_variant	1/7	1	NM_138413.4	P1
HOGA1	ENST00000370647.8	c.107C>T	p.Ala36Val	missense_variant	1/3	1
HOGA1	ENST00000465608.1	n.488C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 43 AN: 249960 Hom.: 0 AF XY: 0.000200 AC XY: 27 AN XY: 135188

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000103 AC: 151 AN: 1461498 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727088

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74318

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000411 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary hyperoxaluria type 3 Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 04, 2022	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 30, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Oct 27, 2023	Biochemical confirmation. ACMG: PS3 PM2 PM3 PP4 -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.17	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.026	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.73	N;N;.
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.42	N;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.038	D;T;D
Sift4G	Benign	0.064	T;T;D
Polyphen		0.30	B;B;.
Vest4		0.26
MVP		0.69
MPC		0.080
ClinPred		0.61	D
GERP RS		4.0
Varity_R		0.24
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201803986; hg19: chr10-99344567; COSMIC: COSV53967364; COSMIC: COSV53967364;