Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SLC3A1 : cystinuria (disease)

HGNC:11025 | MONDO_0009067
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 6
11.5
12
Bisceglia L et al. 1996 Oct (PMID:8792820); Saadi I et al. 1998 Jul (PMID:9648062); Kim JH et al. 2017 Feb (PMID:28049243); Skopková Z et al. 2005 Sep (PMID:16138908);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 5
3.6
Calonge MJ et al. 1994 Apr (PMID:8054986); Bisceglia L et al. 1996 Oct (PMID:8792820); Yuen YP et al. 2006 Jan (PMID:16374432); Skopková Z et al. 2005 Sep (PMID:16138908);
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.33 1
Calonge MJ et al. 1994 Apr (PMID:8054986);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.33    
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
1.5
Lee WS et al. 1993 May (PMID:8486766);
Protein Interaction 0.5 0 - 2 1 0.5
Bartoccioni P et al. 2008 Jun 15 (PMID:18332091);
Expression 0.5 0 - 2 1 0.5
Lee WS et al. 1993 May (PMID:8486766);
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 4 4
Peters T et al. 2003 Sep 1 (PMID:12923163); Henthorn PS et al. 2000 Oct (PMID:11129328);
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) 5.5

 


 

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 5.5 17.5 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
07/26/2019
EXPERT CURATION (DATE)
Definitive
07/26/2019
EVIDENCE SUMMARY
SLC3A1 was first reported in relation to autosomal recessive cystinuria in 1994 (Calonge MJ, et al., PMID: 8054986). At least 236 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) 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 6 publications (PMIDs: 8054986, 8792820, 16374432, 16138908, 9648062, 28049243). Variants in this gene segregated with disease in three additional family members. More evidence is available in the literature, but the maximum score for genetic evidence has been reached. This gene-disease relationship is supported by the biochemical function of SLC3A1 in a cystine, ornithine, arginine, and lysine transporter protein complex (PMID: 8486766), its interaction with b(0,+)AT in that complex (PMID: 18332091), and its expression in the kidneys (PMID: 8486766), where the protein complex absorbs cystine, ornithine, arginine, and lysine back into the blood during urine formation. This gene-disease relationship is further supported by mouse and canine models which recapitulate the elevated urinary cystine, ornithine, arginine, and lysine levels associated with abnormal function of this protein, leading to formation of cystine crystals and stones in the bladder or kidneys. In summary, SLC3A1 is definitively associated with autosomal recessive cystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.