Gene Validity Classification Summary

Gene/Disease Pair:

NSD1 : Sotos syndrome

HGNC:14234 | MONDO_0019349
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Expert Panel: Autism and Intellectual Disability EP
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 7
Douglas J et al. 2003 Jan (PMID:12464997);
Proband with predicted or proven null variant 1.5 0-2 10 6 3 3
Kurotaki N et al. 2002 Apr (PMID:11896389); Douglas J et al. 2003 Jan (PMID:12464997); Höglund P et al. 2003 Jan (PMID:12525543);
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
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 1 0.5
Visser R et al. 2012 Nov 14 (PMID:23155469);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 1 0.5
Qiao Q et al. 2011 Mar 11 (PMID:21196496);
Models Non-human model organism 2 0 - 4 4 1 0 0
Migdalska AM et al. 2012 Dec (PMID:22926222);
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) 1



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 1 13 YES
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
The relationship between NSD1 and Sotos Syndrome (autosomal dominant) was evaluated using the ClinGen Clinical Validity Framework as of 10/15/2018. Variants in NSD1 were first reported in humans with this disease as early as 2002 (Kurotaki et al. ). Evidence supporting this gene-disease relationship includes case-level and experimental data. Over 300 unique pathogenic variants (including missense, splicing, nonsense, frameshift and large deletions) have been reported in ClinVar. Variants in this gene have been reported in at least 8 probands in 2 publications (PMIDs 12464997 and 12525543). Variants in this gene usually occur de novo but can be inherited (e.g Hoglund et al 2003). Microdeletions that encompass the entire NSD1 gene are a common cause of Sotos Syndrome and tend to be associated with more severe learning disability than intragenic pathogenic variants (Tatton-Brown et al. 2005). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is haploinsufficiency (Kurotaki et al. 2002). This gene-disease association is supported by expression studies and in vitro functional assays. In summary, NSD1 is definitively associated with Autosomal Dominant Sotos 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 10/26/2018.