NHLRC1 was first reported in relation to autosomal recessive Lafora disease in 2003 (Chan et al., PMID: 12958597 and PMID: 12960212). At least 85 unique variants (e.g. missense, nonsense, frameshift, deletion, etc.) have been reported in humans (see http://projects.tcag.ca/lafora). Evidence supporting this gene-disease relationship includes case-level data and experimental data. The mechanism for disease is homozygous loss of function (PMID: 21505799). This gene has not been implicated in any other disease associations.
GENETIC EVIDENCE: Summary of Case Level Data: 12 POINTS Variants in this gene have been reported in at least 21 probands in 7 publications (PMIDs: 16190947, 12958597, 16529633, 15781812, 22047982, 18256682, 18263761). Variants in this gene segregated with disease in at least 38 additional family members. Of note, the presence of Lafora bodies by biopsy or on autopsy was considered supporting evidence for the function effect of non-null variants. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
EXPERIMENTAL EVIDENCE This gene-disease association is supported by (animal models and in vitro functional assays, etc.)
In summary, NHLRC1 is definitively associated with autosomal recessive Lafora disease. 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 Epilepsy Working Group on 3/3/2020 using (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.