ClinVar

Description

Variant summary: LMBRD1 c.1056delG (p.Asn353IlefsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and is associated with Methylmalonic aciduria & homocystinuria in HGMD. The variant allele was found at a frequency of 0.00046 in 248514 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LMBRD1 causing Methylmalonic Acidemia With Homocystinuria (0.00046 vs 0.00079), allowing no conclusion about variant significance. c.1056delG has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia With Homocystinuria and the variant segregated with disease (examples: Rutsch_2009 and Miousse_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Rutsch_2009). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.