Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CTH : cystathioninuria (disease)

HGNC:2501 | MONDO_0009058
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 4
Wang J et al. 2003 Apr (PMID:12574942); Kraus JP et al. 2009 Aug (PMID:19428278);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 7
Wang J et al. 2003 Apr (PMID:12574942); Kraus JP et al. 2009 Aug (PMID:19428278); Espinós C et al. 2010 Dec (PMID:20584029);
Segregation Evidence   Summed LOD Family Count  
Candidate gene sequencing
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score    
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) 11
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
Stipanuk MH et al. 1986 (PMID:3524616);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 2 3 3
Yamada H et al. 2012 May 1 (PMID:22387178); Ishii I et al. 2010 Aug 20 (PMID:20566639);
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) 3.5



Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
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
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 11 3.5 14.5 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between CTH and Cystathioninuria (Autosomal Recessive) was evaluated using the ClinGen Clinical Validity Framework as of 04/17/19. Variants in CTH were first reported in humans with this disease as early as 2003 (Wang et al, PMID: 12574942). At least 6 unique variants and one large deletion have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 11 probands in 3 publications (PMIDs: 20584029, 19428278, 12574942). This gene-disease association is supported by a mouse model of Cystathioninuria. The biochemical function of cystathionine gamma-lyase, which is the enzyme responsible for catalyzing the cystathionine to cysteine reaction, is also supportive of a role in the disease. In summary, CTH is definitively associated with Cystathioninuria (Autosomal Recessive). This has been repeatedly demonstrated in both the functional research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on 6/14/19 (SOP Version 6).