Gene Validity Curation

Gene Validity Classification Summary

Gene/Disease Pair:

BLM : Bloom syndrome

HGNC:1058 | MONDO_0008876
Mode of Inheritance: Autosomal recessive inheritance (HP:0000007)
Expert Panel: Hereditary Cancer
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 4
Ellis NA et al. 1995 Nov 17 (PMID:7585968); German J et al. 2007 Aug (PMID:17407155);
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5 2
Ellis NA et al. 1995 Nov 17 (PMID:7585968);
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 1
Lindor NM et al. 2000 Jan 31 (PMID:10678659);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2 2 1.5
Ellis NA et al. 1995 Nov 17 (PMID:7585968); German J et al. 2007 Aug (PMID:17407155);
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
Goss KH et al. 2002 Sep 20 (PMID:12242442); Luo G et al. 2000 Dec (PMID:11101838);
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) 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)*
There has been substantial evidence published associating the BLM gene with Bloom syndrome since the gene-disease relationship was first proposed by Ellis et al. (1995). Multiple case level studies have been performed with BS patients that have variants in the BLM gene. WRN and RECQL4, another two RecQ DNA helicases, are associated with Werner and Rothmund–Thomson syndromes. All three are disorders of chromosomal instability and manifest growth retardation, and predisposition to malignancies. Northern blot analysis of mRNAs derived from selected Bloom’s syndrome cell lines showed absent or abnormal BLM RNA. Multiple BLM deficient mouse models have been established to show consistent phenotypes with BS patients, especially increased rate of SCE and the development of a wide spectrum of cancer. All of these types of evidence combined are consistent with a definitive relationship between the BLM gene and Bloom Syndrome (BS).