Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

FMR1 : fragile X syndrome

HGNC:3775 | MONDO_0010383
Mode of Inheritance: X-linked inheritance (HP:0001417)
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 3
Lugenbeel KA et al. 1995 Aug (PMID:7670500); Quartier A et al. 2017 Apr (PMID:28176767); De Boulle K et al. 1993 Jan (PMID:8490650);
Proband with predicted or proven null variant 1.5 0-2 10 6 8.5 8.5
Gr√łnskov K et al. 2011 Apr (PMID:21267007); Lugenbeel KA et al. 1995 Aug (PMID:7670500); Quartier A et al. 2017 Apr (PMID:28176767); Okray Z et al. 2015 Apr (PMID:25693964); Meijer H et al. 1994 Apr (PMID:8069307); Kremer EJ et al. 1991 Jun 21 (PMID:1675488);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 1
Myrick LK et al. 2014 Oct (PMID:24448548);
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 3 1.5
Abitbol M et al. 1993 Jun (PMID:8348153); Hinds HL et al. 1993 Jan (PMID:8490651); Devys D et al. 1993 Aug (PMID:8401578);
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1 4 2
Myrick LK et al. 2014 Oct (PMID:24448548); Feng Y et al. 1997 Dec (PMID:9659908); Laggerbauer B et al. 2001 Feb 15 (PMID:11157796);
Models Non-human model organism 2 0 - 4 4 2 2 2.5
Anonymous et al. 1994 Jul 15 (PMID:8033209); Zang JB et al. 2009 Dec (PMID:20011099);
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 1 0.5
Myrick LK et al. 2014 Oct (PMID:24448548);
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)*
FMR1 was first reported in relation to X-linked fragile X syndrome in 1991 (Kremer et al., 1675488). The majority of cases are a result of an unstable expanded trinucleotide (CGG)n repeat sequence of greater than 200 repeats in the 5-prime untranslated region of FMR1; however, at least 10 unique variants (repeat expansion, missense, splice, nonsense, frameshift, insertion and large deletions) have been reported in humans. Other phenotypic presentations (Fragile X Tremor Ataxia Syndrome, Primary Ovarian Insufficiency) may be observed in individuals with FMR1 premutations (defined as 55-200 repeats). For the purposes of this curation, however, we have chosen to only evaluate evidence related to classic Fragile X syndrome. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in at least 10 probands in 8 publications (1675488, 8490650, 8069307, 7670500, 21267007, 24448548, 25693964, 28176767). 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 hemizygous loss of function. This gene-disease association is supported by animal models, expression studies and functional assays. In summary, FMR1 is definitively associated with X-linked fragile X 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 Intellectual Disability and Autism Working Group on 6/3/2019 (SOP Version 6).