ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with spinal muscular atrophy, lower extremity-predominant 1 (MIM#158600), intellectual disability (MIM#614563) and Charcot-Marie-Tooth disease, axonal, type 20 (MIM#614228). While there is no clear genotype-phenotype correlation, there is some association between the severity of the variant on protein function and the phenotype that is manifested (PMID: 25512093, PMID: 28196890). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 25512093). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (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) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic. It has been shown to segregate within families, and arise de novo, in individuals with spinal muscular atrophy or spinal muscular atrophy with lower extremity predominant (ClinVar, PMID: 25512093, PMID: 28554554). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of patient lymphoblasts indicated an increased binding in adaptor protein BICD2 (PMID: 25512093). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign