Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

HGD : alkaptonuria

HGNC:4892 | MONDO_0008753
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Aminoacidopathy
SOP: Gene Clinical Validity Standard Operating Procedures (SOP), Version 6

Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12 2
3
12
Beltrán-Valero de Bernabé D et al. 1998 Apr (PMID:9529363); Gehrig A et al. 1997 (PMID:9154114);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 11
11
Fernández-Cañón JM et al. 1996 Sep (PMID:8782815); Beltrán-Valero de Bernabé D et al. 1998 Apr (PMID:9529363); Gehrig A et al. 1997 (PMID:9154114);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 8.02 2
Fernández-Cañón JM et al. 1996 Sep (PMID:8782815); Ramos SM et al. 1998 Jun 30 (PMID:9674916);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 8.02    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
1
KNOX WE et al. 1955 Oct (PMID:13271328);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 1 0.5
Fernández-Cañón JM et al. 1996 Sep (PMID:8782815);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 1 1
Montagutelli X et al. 1994 Jan 1 (PMID:8188247);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 2

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 2 14 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
02/11/2019
EXPERT CURATION (DATE)
Definitive
02/08/2019
EVIDENCE SUMMARY
HGD was first reported in relation to autosomal recessive inheritance of alkaptonuria in 1996 (Fernández-Cañón JM, et al., 1996, PMID: 8782815). At least 115 unique variants (including many missense and nonsense, several splicing, and some frameshift, etc.) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 14 probands in 4 publications (PMIDs: 8782815, 9529363, 9154114, 9674916). Variants in this gene segregated with disease in 18 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by the biochemical function of HGD, its expression in the liver, and a mouse model which displays high levels of urinary homogentisic acid, as observed in humans (PMIDs: 13271328, 8782815, 8188247). HGD functions in phenylalanine and tyrosine metabolism to convert homogentisate to maleylacetoacetate; in the absence of HGD activity accumulation of homogentisate results in alkaptonuria. In summary, HGD is definitively associated with autosomal recessive inheritance of alkaptonuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.