rs749272546

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_018368.4(LMBRD1):c.1056del(p.Asn353IlefsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,602,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00061 ( 0 hom. )

Consequence

LMBRD1
NM_018368.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11O:1

Conservation

PhyloP100: 0.576

Variant links:

Genes affected

LMBRD1 (HGNC:23038): (LMBR1 domain containing 1) This gene encodes a lysosomal membrane protein that may be involved in the transport and metabolism of cobalamin. This protein also interacts with the large form of the hepatitis delta antigen and may be required for the nucleocytoplasmic shuttling of the hepatitis delta virus. Mutations in this gene are associated with the vitamin B12 metabolism disorder termed, homocystinuria-megaloblastic anemia complementation type F.[provided by RefSeq, Oct 2009]

LMBRD1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-69701469-TC-T is Pathogenic according to our data. Variant chr6-69701469-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 225048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-69701469-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
LMBRD1	NM_018368.4 linkuse as main transcript	c.1056del	p.Asn353IlefsTer18	frameshift_variant	11/16	ENST00000649934.3
LMBRD1	NM_001363722.2 linkuse as main transcript	c.837del	p.Asn280IlefsTer18	frameshift_variant	11/16
LMBRD1	NM_001367271.1 linkuse as main transcript	c.837del	p.Asn280IlefsTer18	frameshift_variant	11/16
LMBRD1	NM_001367272.1 linkuse as main transcript	c.837del	p.Asn280IlefsTer18	frameshift_variant	11/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMBRD1	ENST00000649934.3 linkuse as main transcript	c.1056del	p.Asn353IlefsTer18	frameshift_variant	11/16		NM_018368.4	P2	Q9NUN5-1

Frequencies

GnomAD3 genomes

AF:

0.000586

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000463

AC:

115

AN:

248514

Hom.:

AF XY:

0.000513

AC XY:

AN XY:

134444

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000698

Gnomad NFE exome

AF:

0.000854

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000612

AC:

888

AN:

1450816

Hom.:

Cov.:

AF XY:

0.000634

AC XY:

458

AN XY:

722398

show subpopulations

Gnomad4 AFR exome

AF:

0.000121

Gnomad4 AMR exome

AF:

0.0000450

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000470

Gnomad4 NFE exome

AF:

0.000761

Gnomad4 OTH exome

AF:

0.000284

GnomAD4 genome

AF:

0.000586

AC:

AN:

151964

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.00111

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000606

Hom.:

Bravo

AF:

0.000397

EpiCase

AF:

0.000601

EpiControl

AF:

0.000891

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Methylmalonic aciduria and homocystinuria type cblF

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 24, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 21, 2018	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] -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 30, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	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) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2013

- -

Cobalamin C disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 08, 2022

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. -

Disorders of Intracellular Cobalamin Metabolism

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over