ClinVar

Description

0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function has been associated encephalopathy, progressive, with or without lipodystrophy (MIM#615924) and lipodystrophy, congenital generalized, type 2 (MIM#269700). A gain of function mechanism has been associated with neuropathy, distal hereditary motor, type VC (MIM#619112) and Silver spastic paraplegia syndrome (MIM#270685; PMID: 14981520). (I) 0108 - This gene is associated with both recessive and dominant disease. There is emerging evidence of a dominant form of epileptic encephalopathy associated with this gene (PMID: 31369919). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to arginine. (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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another variant type variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative missense change to alanine has been reported in an individual with early-onset epileptic encephalopathy (PMID: 35290466). The alanine change has also been reported in ClinVar as a VUS. A second alternative missense change to leucine has been reported in LOVD as a VUS. (SP) 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) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign