ClinVar Miner

Submissions for variant NM_018368.4(LMBRD1):c.1056del (p.Asn353fs) (rs749272546)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000210618 SCV000262941 pathogenic Inborn genetic diseases 2013-11-06 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000255705 SCV000610635 pathogenic not provided 2017-08-30 criteria provided, single submitter clinical testing
GeneDx RCV000255705 SCV000322299 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing The c.1056delG pathogenic variant in the LMBRD1 gene has been reported previously in the homozygous and compound heterozygous state in individuals with LMBRD1-related disorders. Individuals homozygous for the c.1056delG variant showed phenotypic variability ranging from neonatal death, failure to thrive, developmental delay, feeding difficulties, heart defects, short stature, and impaired coordination, to asymptomtic with therapy (Rutsch et al., 2009). The c.1056delG variant causes a frameshift starting with codon Asparagine 353, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Asn353IlefsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1056delG variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.1056delG as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778799 SCV000915179 pathogenic METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblF TYPE 2017-10-24 criteria provided, single submitter clinical testing 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.
Invitae RCV000778799 SCV000958342 pathogenic METHYLMALONIC ACIDURIA AND HOMOCYSTINURIA, cblF TYPE 2018-08-20 criteria provided, single submitter clinical testing 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. This variant is present in population databases (rs749272546, ExAC 0.1%). This variant has been reported as homozygous or in combination with another LMBRD1 variant in individuals affected with Cobalamin F (cblF) deficiency (PMID: 19136951, 21303734, 23776111, 26997947). This variant is also described as a founder mutation of European ancestry (PMID: 19136951). ClinVar contains an entry for this variant (Variation ID: 225048). Loss-of-function variants in LMBRD1 are known to be pathogenic (PMID: 19136951, 21303734). For these reasons, this variant has been classified as Pathogenic.

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