Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788193 | SCV005398618 | uncertain significance | Familial temporal lobe epilepsy 7 | 2022-02-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with familial temporal lobe epilepsy, 7 (ADTLE; MIM#616436), lissencephaly 2 (Norman-Roberts type) (MIM#257320) and autism spectrum disorder (ASD). The mechanism associated with myoclonus dystonia is currently unknown. Gain of function and dominant negative have also been suggested as mechanisms associated with neuronal migration disorders (Riva et al. bioRxiv). (I) 0108 - This gene is associated with both recessive and dominant disease. This gene is associated with autosomal dominant ADTLE (MIM#616436), ASD and myoclonus dystonia and autosomal recessive lissencephaly 2 (Norman-Roberts type) (MIM#257320). It should be noted, however, that one compound heterozygous ASD individual has been reported (PMID: 28419454). More recently, missense variants in this gene have been reported in individuals with neuronal migration disorders encompassing pachygyria, polymicrogyria and heterotopia (Riva et al. bioRxiv). (I) 0112 - The condition associated with this gene has incomplete penetrance. Incomplete penetrance has been reported for ADTLE and ASD (OMIM, PMID: 26046367, PMID: 27064498). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to valine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated C-terminal subrepeat of tandem repeat unit 7 (NCBI conserved domain). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |