rs397509360

Positions:

• chr10-97611611-TGAG-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM4_Supporting PP5_Very_Strong

The NM_138413.4(HOGA1):​c.944_946del​(p.Glu315del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,614,020 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: HOGA1 NM_138413.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 8.99

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_138413.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-97611611-TGAG-T is Pathogenic according to our data. Variant chr10-97611611-TGAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 29.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-97611611-TGAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HOGA1	NM_138413.4	c.944_946del	p.Glu315del	inframe_deletion	7/7	ENST00000370646.9	NP_612422.2
HOGA1	NM_001134670.2	c.455_457del	p.Glu152del	inframe_deletion	3/3		NP_001128142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HOGA1	ENST00000370646.9	c.944_946del	p.Glu315del	inframe_deletion	7/7	1	NM_138413.4	ENSP00000359680	P1
HOGA1	ENST00000370647.8	c.455_457del	p.Glu152del	inframe_deletion	3/3	1		ENSP00000359681

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000466 AC: 117 AN: 251206 Hom.: 0 AF XY: 0.000427 AC XY: 58 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00914

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1461798 Hom.: 1 AF XY: 0.000267 AC XY: 194 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000350 AC XY: 26 AN XY: 74372

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.000332

EpiCase AF: 0.000327

EpiControl AF: 0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary hyperoxaluria type 3 Pathogenic:11 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 10, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 19, 2018	The HOGA1 c.944_946delAGG (p.Glu315del) variant results in an inframe deletion. Across a selection of the available literature, the p.Glu315del variant has been identified in a total of 38 individuals with primary hyperoxaluria including 15 homozygotes and 23 compound heterozygotes (Belostotsky et al. 2010; Monico et al. 2011; Williams et al. 2012; Hopp et al. 2015; Pitt et al. 2015; Williams et al. 2015). The second variant carried by the compound heterozygotes is either a missense or splice_region variant. The p.Glu315del variant was absent from 113 controls and is reported at a frequency of 0.008967 in the Ashkenazi Jewish population of the Genome Aggregation Database. Expression of the p.Glu315del variant protein in CHO cells revealed that the protein was mislocalized and retained no measurable activity (Riedel et al. 2012). Expression analysis in HEK293 cells demonstrated the p.Glu315del variant protein was unstable and was only detected in the presence of 26S proteasome inhibitor (MacDonald et al. 2016). Based on the collective evidence, the p.Glu315del variant is classified as pathogenic for primary hyperoxaluria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 07, 2018	The p.Glu315del variant in HOGA1 is an established pathogenic variant associated with primary hyperoxaluria type III. It is one of the two most commonly observe d pathogenic variants in HOGA1 and has been identified in the homozygous or comp ound heterozygous state in multiple affected individuals and segregated with dis ease in multiple affected family members (Belostotsky 2010, Monico 2011, William s 2012, Hopp 2015). It is prevalent in the Ashkenazi Jewish population and has b een identified in 0.9% of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad. broadinstitute.org). In vitro functional studies suggest that this variant impac ts protein function (MacDonald 2016). In summary, this variant meets our criteri a to be classified as pathogenic for primary hyperoxaluria type III in an autoso mal recessive manner. ACMG/AMP Criteria applied: PP1_Very Strong, PS3_Moderate. PM4_Supporting. -
Pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_138413.3:c.944_946delAGG in the HOGA1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. Belostotsky et al. reported that three independent families harboring homozygous for this variant, leading to the loss of one glutamic acid residue (PMID: 20797690). In addition, Monico et al. reported mutiple patients are compound heterozygous with another pathogenic variant and segregated (PMID: 21896830). Experimental studies have shown that this missense change leads to HOGA1 protein instability (PMID: 22771891; 27096395). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3_VeryStrong; PS3. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_138413.3(HOGA1):c.944_946delAGG(E315del) is classified as pathogenic in the context of primary hyperoxaluria type 3. Sources cited for classification include the following: PMID 20797690, 22771891, 22391140 and 21896830. Classification of NM_138413.3(HOGA1):c.944_946delAGG(E315del) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2023	Variant summary: HOGA1 c.944_946delAGG (p.Glu315del) results in an in-frame deletion that is predicted to remove one amino acid (Gly315) from the encoded protein. The variant allele was found at a frequency of 0.00047 in 251206 control chromosomes (gnomAD) and is prevalent in individuals of Ashkenazi Jewish ancestry (found at a frequency of 0.0091). c.944_946delAGG has been reported in the literature in the homozygous and compound heterozygous state in multiple individuals affected with Primary Hyperoxaluria, Type III and has been found to segregate with disease within families (e.g. Belostotsky_2010). These data indicate that the variant is very likely to be associated with disease. Experimental studies have found that the variant results in a protein that is unstable, is rapidly degraded, and retains no measurable enzymatic activity in vitro (e.g.Riedel_2012, MacDonald_2016). Nine submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Biochemistry Laboratory, Health Services Laboratory	Oct 27, 2023	ACMG:PS3 PM3 PM4 PP1 PP4 PP5 -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This variant, c.944_946del, results in the deletion of 1 amino acid(s) of the HOGA1 protein (p.Glu315del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758714937, gnomAD 0.9%). This variant has been observed in individual(s) with hyperoxaluria (PMID: 20797690). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 20797690). ClinVar contains an entry for this variant (Variation ID: 29). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HOGA1 function (PMID: 22771891, 27096395). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	HOGA1: PM3:Strong, PM2, PM4:Supporting, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 26, 2023	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate targeted cellular degradation and an absence of HOGA1 protein (MacDonald et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22391140, 22771891, 27096395, 20797690, 31980526, 34426522, 31589614) -

HOGA1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2023

The HOGA1 c.944_946delAGG variant is predicted to result in an in-frame deletion (p.Glu315del). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with primary hyperoxaluria type III (see for example, Table 2, Belostotsky et al. 2010. PubMed ID: 20797690; Table 2, Williams et al. 2012. PubMed ID: 22391140; Table 3, Williams et al. 2015. PubMed ID: 25629080). This variant has been reported as one of the most common variants that causes primary hyperoxaluria type III (Figure 1, Hopp et al. 2015. PubMed ID: 25644115). In vitro experimental studies suggest this variant affects protein function leading to preferential degradation through the ubiquitin proteasome pathway (Riedel et al. 2012. PubMed ID: 22771891; Figure 4, MacDonald et al. 2016. PubMed ID: 27096395). This variant is reported in 0.90% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-99371368-TGAG-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397509360; hg19: chr10-99371368;