rs80356682
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000228.3(LAMB3):c.1903C>T(p.Arg635Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R635R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000228.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LAMB3 | NM_000228.3 | c.1903C>T | p.Arg635Ter | stop_gained | 14/23 | ENST00000356082.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.1903C>T | p.Arg635Ter | stop_gained | 14/23 | 1 | NM_000228.3 | P1 | |
LAMB3 | ENST00000367030.7 | c.1903C>T | p.Arg635Ter | stop_gained | 14/23 | 1 | P1 | ||
LAMB3 | ENST00000391911.5 | c.1903C>T | p.Arg635Ter | stop_gained | 13/22 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000467 AC: 71AN: 152164Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000509 AC: 128AN: 251368Hom.: 0 AF XY: 0.000434 AC XY: 59AN XY: 135902
GnomAD4 exome AF: 0.000706 AC: 1032AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.000659 AC XY: 479AN XY: 727218
GnomAD4 genome ? AF: 0.000467 AC: 71AN: 152164Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22AN XY: 74346
ClinVar
Submissions by phenotype
not provided Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Arg635*) in the LAMB3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMB3 are known to be pathogenic (PMID: 11023379, 16473856). This variant is present in population databases (rs80356682, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with autosomal recessive epidermolysis bullosa (PMID: 7698759, 11689492, 15311214, 15663509, 27062385, 28830826). ClinVar contains an entry for this variant (Variation ID: 14539). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 25, 2020 | Reported in multiple individuals with junctional epidermolysis bullosa (JEB) as the single most common JEB pathogenic variant representing 40% of the disease alleles in Caucasian patients with JEB (Pulkkinen et al., 1994; Varki et al., 2006); Nonsense 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: 27062385, 11298117, 20301304, 12366701, 11689492, 25525159, 7698759, 16473856, 11451332, 25708563, 27375110, 15311214, 15663509, 26990548, 9205497, 9209887, 8824879, 28830826, 31980526, 31589614, 32484238, 33274474) - |
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:6Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | Apr 28, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 27, 2016 | Variant summary: The LAMB3 c.1903C>T (p.Arg635X) variant results in a premature termination codon, predicted to cause a truncated or absent LAMB3 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 92/121034 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0013392 (89/66456). This variant has been reported in numerous JEB patients both as homozygotes and compound heterozygotes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Mar 03, 2016 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000228.2(LAMB3):c.1903C>T(R635*) is classified as pathogenic in the context of LAMB3-related Herlitz junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 16473856, 17476356, 16473856, 11023379 and 8983017. Classification of NM_000228.2(LAMB3):c.1903C>T(R635*) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jun 23, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop gained p.R635* in LAMB3 (NM_000228.3) have been reported previously in multiple patients associated with severe Herlitz phenotype (Nakano et al 2000; Cserhalmi-Friedman et al 2001). The variant has been reported to ClinVar as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. The p.R635* variant is a loss of function variant in the gene LAMB3, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000219.2:p.L11Pfs*43 and 47 others. For these reasons, this variant has been classified as Pathogenic. - |
Junctional epidermolysis bullosa gravis of Herlitz;C0268374:Junctional epidermolysis bullosa, non-Herlitz type;C4011403:Amelogenesis imperfecta type 1A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | LAMB3 NM_000228.2 exon 14 p.Arg635* (c.1903C>T): This variant has been reported in the literature in several individuals with epidermolysis bullosa in the homozygous and compound heterozygous state, including an entry in GeneReviews. Literature suggests that this variant is one of the most common pathogenic variants in this gene (Pulkkinen 1994 PMID:7698759, Kivirikko 1996 PMID:8824879, Varki 2006 PMID:16473856, Pfendner 2014 PMID:20301304). This variant is present in 0.1% (133/129106) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-209799066-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, autosomal recessive inheritance carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:14539). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies also support that this variant will impact the protein (Pulkkinen 1994 PMID:7698759). This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Varki 2006 PMID:16473856). In summary, this variant is classified as pathogenic. - |
LAMB3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 21, 2023 | The LAMB3 c.1903C>T variant is predicted to result in premature protein termination (p.Arg635*). This variant has been reported, in the homozygous or compound heterozygous state, in individuals affected with Herlitz type of junctional epidermolysis bullosa (see for example, Kivirikko et al. 1996. PubMed ID: 8824879; Pulkkinen et al. 1997. PubMed ID: 9242513; Christiano et al. 1997. PubMed ID: 9160387; Yuen et al. 2011. PubMed ID: 21801158). It is considered one of the most common causative variants for junctional epidermolysis bullosa (Varki et al. 2006. PubMed ID: 16473856). This variant is reported in 0.10% of alleles in individuals of European (Non-Finnish) descent in gnomAD, and it is interpreted as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/14539/). Nonsense variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Junctional epidermolysis bullosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 02, 2018 | The LAMB3 c.1903C>T (p.Arg635Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg635Ter variant occurs in a region of the gene described as a mutational hotspot (Kivirikko et al. 1996; Pulkkinen et al. 1997). Nanako et al. (2000) noted that the p.Arg635Ter variant was present in 45.4% of disease-associated LAMB3 alleles in a review of a database of junctional epidermolysis bullosa(JEB) variants. Across a selection of the available literature, the p.Arg635Ter variant has been identified in 14 probands in a homozygous state and in 20 probands in a compound heterozygous state, most often associated with the severe Herlitz phenotype (Pulkkinen et al. 1994; Kivirikko et al. 1996; Pulkkinen et al. 1997; Nakano et al. 2000; Cserhalmi-Friedman et al. 2001; Gache et al. 2001; Hauschild et al. 2001). Segregation of the variant with the disease was shown in two studies (Pulkkinen et al. 1994; Gache et al. 2001). The p.Arg635Ter variant is reported at a frequency of 0.00134 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg635Ter variant is classified as pathogenic for junctional epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at