Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

CBS : classic homocystinuria

HGNC:1550 | MONDO_0009352
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
Li DX et al. 2018 Apr (PMID:29508359); Katsushima F et al. 2006 Apr (PMID:16307898); Urreizti R et al. 2003 Jul (PMID:12815602); Kozich V et al. 1992 (PMID:1301198);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 11
Gong B et al. 2015 Dec 15 (PMID:26667307); Suri F et al. 2014 Dec 15 (PMID:25455305); Katsushima F et al. 2006 Apr (PMID:16307898); Sebastio G et al. 1995 Jun (PMID:7762555); de Franchis R et al. 1999 (PMID:10408774); Urreizti R et al. 2003 Jul (PMID:12815602);
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 5.58 3
Gong B et al. 2015 Dec 15 (PMID:26667307); Suri F et al. 2014 Dec 15 (PMID:25455305); Sebastio G et al. 1995 Jun (PMID:7762555);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 5.58    
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
SELIM AS et al. 1959 Jun (PMID:13654400);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 1
Melenovsk√° P et al. 2015 Mar (PMID:25331909);
Non-patient cells 0.5 0 - 1 1 0.5
Shan X et al. 1998 May (PMID:9590298);
Models Non-human model organism 2 0 - 4 4 1 3 4
Gupta S et al. 2009 Mar (PMID:18987302);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Majtan T et al. 2018 Mar 7 (PMID:29398487);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 6



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 12 6 18 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between CBS and classic homocysteinuria, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 26th, 2019. CBS encodes cystathione beta-synthase which catalyses the first step of the transsulfuration pathway, from homocysteine to cystathione. Variants in CBS were first reported in humans with this disorder in 1992 (Kozich and Kraus, PMID 1301198). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (Kozich and Kraus, 1992, PMID 1301198; De Franchis et al, 1999, PMID 10408774; Sebastio et al, 1999, PMID 7762555; Urreizti et al, 2003, PMID 12815602; Katsushima et al, 2006, PMID 16307898; Suri et al, 2014, PMID 25455305; Gong et al, 2015, PMID 26667307; Li et al, 2018, PMID 29508359). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (Selim et al, 1959, PMID 13654400; Jhee and Kruger, 2005, PMID 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (Shan et al, 1998, PMID 9590298; Melenovsk√° et al, 2018, PMID 25331909), as well as the biochemical and clinical features of mouse models (Gupta et al, 2009, PMID 18987302) and enzyme replacement studies in mice (Matjan et al, 2018, PMID 29398487). More information is available but the maximum experimental evidence score (6 points) has been reached. In summary, CBS is definitively associated with classic homocystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 12, 2019.