Gene Validity Curation

SMC1A - complex neurodevelopmental disorder

Gene: SMC1A (HGNC:11111)
Classification - 06/19/2019
Disease: complex neurodevelopmental disorder (MONDO_0100038)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Intellectual Disability and Autism
Evidence Summary: The SMC1A gene has been associated with X-linked complex neurodevelopmental disorder. Variants in SMC1A have been reported in humans as early as 1995 (7757075, 7757074, 7757076). This disease association was made using case-level data and experimental data. At least 20 missense, 1 splicing, and 5 small deletions have been reported in humans. Variants have been found in at least 28 probands in 5 publications (28166369, 26752331, 24124034, 1660407, 19701948). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by patient cells functional alteration and protein interactions. In summary, SMC1A is definitively associated with X-linked complex neurodevelopmental disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (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 10
10
10
Ansari M et al. 2014 Oct (PMID:25125236); Pié J et al. 2010 Apr (PMID:20358602); Deardorff MA et al. 2007 Mar (PMID:17273969);
Proband with predicted or proven null variant 1.5 0-2 10 8 8 8
Symonds JD et al. 2017 Apr (PMID:28166369);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 13
3.5
3.5
Jang MA et al. 2015 Nov (PMID:26354354); Symonds JD et al. 2017 Apr (PMID:28166369); Gervasini C et al. 2013 Nov (PMID:24124034); Musio A et al. 2006 May (PMID:16604071); Deardorff MA et al. 2007 Mar (PMID:17273969);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 0 0  
Candidate gene sequencing 1.51 1
Musio A et al. 2006 May (PMID:16604071);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 1.51    
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
0.5
Protein Interaction 0.5 0 - 2 1 0.5
Sumara I et al. 2000 Nov 13 (PMID:11076961);
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 2
2
2
Revenkova E et al. 2009 Feb 1 (PMID:18996922);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4
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) 2.5

 


 

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 2.5 14.5 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
09/30/2019
EXPERT CURATION (DATE)
Definitive
06/19/2019
EVIDENCE SUMMARY
The SMC1A gene has been associated with X-linked complex neurodevelopmental disorder. Variants in SMC1A have been reported in humans as early as 1995 (7757075, 7757074, 7757076). This disease association was made using case-level data and experimental data. At least 20 missense, 1 splicing, and 5 small deletions have been reported in humans. Variants have been found in at least 28 probands in 5 publications (28166369, 26752331, 24124034, 1660407, 19701948). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is supported by patient cells functional alteration and protein interactions. In summary, SMC1A is definitively associated with X-linked complex neurodevelopmental disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panel on 6/19/19 (SOP Version 6).