Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

SHANK3 : Phelan McDermid syndrome

HGNC:14294 | MONDO_0011652
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Intellectual Disability and Autism
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 10
Soorya L et al. 2013 Jun 11 (PMID:23758760); Leblond CS et al. 2014 Sep (PMID:25188300); De Rubeis S et al. 2018 Apr 27 (PMID:29719671);
Proband with predicted or proven null variant 1.5 0-2 10 3 4.5 4.5
Leblond CS et al. 2014 Sep (PMID:25188300); De Rubeis S et al. 2018 Apr 27 (PMID:29719671);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
De Rubeis S et al. 2018 Apr 27 (PMID:29719671);
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  
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) 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
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1
Shcheglovitov A et al. 2013 Nov 14 (PMID:24132240); Halbedl S et al. 2016 Apr (PMID:26725465);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 2 1
Cochoy DM et al. 2015 Apr 29 (PMID:26045941); Durand CM et al. 2012 Jan (PMID:21606927);
Models Non-human model organism 2 0 - 4 4 2 2.5 4
Drapeau E et al. 2018 May-Jun (PMID:30302388); Wang X et al. 2016 May 10 (PMID:27161151);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
Mei Y et al. 2016 Feb 25 (PMID:26886798);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2 1 1
Shcheglovitov A et al. 2013 Nov 14 (PMID:24132240);
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 SHANK3 and Phelan McDermid syndrome (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 11/19/2018. Variants in SHANK3 were first reported in humans with this disease as early as 2001 when a balanced translocation disrupting the SHANK3 gene was reported (Bonaglia et al., PMID:11431708). Also called the 'deletion 22q13.3 syndrome', this disease can be caused by large deletions involving additional genes that are responsible for the varied phenotype and severity amongst individuals (Tabet et al., 2017; PMID: 29263841, De Rubeis et al., 2018; PMID:29719671). At least 14 unique variants (mostly nonsense, frameshift and large deletions) affecting only SHANK3 have been reported in humans with a syndrome that includes intellectual disability, hypotonia and facial dysmorphism. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 15 probands in 4 publications (PMIDs 11431708, 29719671, 25188300, 23758760). Most variants occurred de novo. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Bonaglia et al., PMID:11431708). This gene-disease association is supported by expression studies, in vitro functional assays, rescue experiments and animal models. In summary, SHANK3 is definitively associated with Autosomal Dominant Phelan McDermid syndrome. 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 ID/Autism Working Group on 12/12/2018 (SOP Version 6).