ClinVar Genomic variation as it relates to human health

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This pathogenic variant has been previously reported in patients with methylmalonic aciduria and homocystinuria type cblF (MMAHCF) [PMID 19136951, 24664876, 23776111]

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.

The LMBRD1 c.1056delG (p.Asn353IlefsTer18) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Asn353IlefsTer18 variant has been identified in 11 individuals with disorders of intracellular cobalamin metabolism, including in a homozygous state in eight and in a compound heterozygous state in three (Rutsch et al. 2009; Miousse et al. 2011; Constantinou et al. 2016). An additional deceased proband with cobalamin deficiency was found to carry the p.Asn353IlefsTer18 variant and a second variant in the MTR gene, suggesting the possibility of digenic inheritance (Farwell Gonzalez et al. 2015). Phenotypic symptoms cover a wide range of symptoms including failure to thrive, neutropenia, developmental delay, stomatitis, megaloblastic anemia, and feeding difficulties; however, some patients may show asymptomatic long-term survival (Rutsch et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.00109 in the European American population of the Exome Sequencing Project. Transfection of immortalized fibroblasts from a compound heterozygous proband and a homozygous proband with wildtype LMBD1 was able to rescue the biochemical intracellular cobalamin pathway F (cblF) phenotype (Rutsch et al. 2009). Based on the collective evidence and the potential impact of frameshift variants, the p.Asn353IlefsTer18 variant is classified as pathogenic for disorders of intracellular cobalamin metabolism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24664876, 22065268, 19136951, 26997947, 23776111, 20127417, 21303734, 25533962, 31589614)

This sequence change creates a premature translational stop signal (p.Asn353Ilefs*18) in the LMBRD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LMBRD1 are known to be pathogenic (PMID: 19136951, 21303734). This variant is present in population databases (rs749272546, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Cobalamin F (cblF) deficiency (PMID: 19136951, 21303734, 23776111, 26997947). It is commonly reported in individuals of European ancestry (PMID: 19136951). ClinVar contains an entry for this variant (Variation ID: 225048). For these reasons, this variant has been classified as Pathogenic.

The LMBRD1 c.1056delG variant is predicted to result in a frameshift and premature protein termination (p.Asn353Ilefs*18). This is one of the most commonly reported pathogenic variants in the LMBRD1 gene. It has been reported in both the homozygous and compound heterozygous states in cellularly confirmed methylmalonic acidemia and homocystinuria cblF type patients (e.g., Rutsch et al. 2009. PubMed ID: 19136951; Armour et al. 2013. PubMed ID: 23776111; Miousse et al. 2011. PubMed ID: 21303734). This variant is reported in 0.087% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LMBRD1 are expected to be pathogenic. This variant is interpreted as pathogenic.