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)
ClinVar Genomic variation as it relates to human health
NM_000228.3(LAMB3):c.1903C>T (p.Arg635Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(23)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
23
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000228.3(LAMB3):c.1903C>T (p.Arg635Ter)
Variation ID: 14539 Accession: VCV000014539.63
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1q32.2 1: 209625721 (GRCh38) [ NCBI UCSC ] 1: 209799066 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 3, 2013 Oct 20, 2024 Jan 21, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000228.3:c.1903C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000219.2:p.Arg635Ter nonsense NM_001017402.2:c.1903C>T NP_001017402.1:p.Arg635Ter nonsense NM_001127641.1:c.1903C>T NP_001121113.1:p.Arg635Ter nonsense NC_000001.11:g.209625721G>A NC_000001.10:g.209799066G>A NG_007116.1:g.31755C>T - Protein change
- R635*
- Other names
- -
- Canonical SPDI
- NC_000001.11:209625720:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00049
Trans-Omics for Precision Medicine (TOPMed) 0.00049
The Genome Aggregation Database (gnomAD), exomes 0.00051
Exome Aggregation Consortium (ExAC) 0.00076
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LAMB3 | - | - |
GRCh38 GRCh37 |
1339 | 1373 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2022 | RCV000015638.39 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 1, 2022 | RCV000015639.36 | |
| Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 21, 2024 | RCV000255105.40 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 3, 2022 | RCV000762876.5 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2018 | RCV000778963.5 | |
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LAMB3-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Dec 21, 2023 | RCV003952359.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Pathogenic
(Sep 25, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321863.6
First in ClinVar: Oct 09, 2016 Last updated: Dec 19, 2017 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Jun 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa, non-Herlitz type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV002764770.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Epidermolytic ichthyosis (present) , Erythroderma (present) , Abnormal blistering of the skin (present)
|
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Pathogenic
(Mar 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Amelogenesis imperfecta type 1A
Junctional epidermolysis bullosa, non-Herlitz type Junctional epidermolysis bullosa gravis of Herlitz
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893256.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Junctional epidermolysis bullosa gravis of Herlitz
Junctional epidermolysis bullosa, non-Herlitz type Amelogenesis imperfecta type 1A
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920143.1
First in ClinVar: Apr 30, 2023 Last updated: Apr 30, 2023 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Jan 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000940529.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa gravis of Herlitz
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695999.1
First in ClinVar: Jan 06, 2018 Last updated: Jan 06, 2018 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Nov 02, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Epidermolysis bullosa, junctional
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915390.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 26, 2019)
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criteria provided, single submitter
Method: clinical testing
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Junctional epidermolysis bullosa gravis of Herlitz
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194089.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(Apr 28, 2021)
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criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa gravis of Herlitz
Affected status: yes
Allele origin:
maternal
|
Centogene AG - the Rare Disease Company
Accession: SCV002059594.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
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Pathogenic
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa gravis of Herlitz
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003836059.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
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Pathogenic
(Dec 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa, non-Herlitz type
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003836089.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Junctional epidermolysis bullosa, non-Herlitz type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100383.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Pretibial dystrophic epidermolysis bullosa (present)
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Pathogenic
(Nov 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002023898.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
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Pathogenic
(Oct 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249933.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
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Pathogenic
(Mar 03, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Junctional epidermolysis bullosa gravis of Herlitz
Affected status: no
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Study: CSER-NextGen
Accession: SCV000538047.1 First in ClinVar: Apr 03, 2017 Last updated: Apr 03, 2017 |
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001740146.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954779.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jan 01, 2005)
|
no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA, JUNCTIONAL 1A, INTERMEDIATE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV005046839.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
Comment on evidence:
Severe Junctional Epidermolysis Bullosa 1B In an infant with the Herlitz form of junctional epidermolysis bullosa (JEB1B; 226700), Pulkkinen et al. (1994) identified a homozygous … (more)
Severe Junctional Epidermolysis Bullosa 1B In an infant with the Herlitz form of junctional epidermolysis bullosa (JEB1B; 226700), Pulkkinen et al. (1994) identified a homozygous C-to-T transition in the LAMB3 gene, resulting in an arg635-to-ter (R635X) substitution. Ultrastructural and immunofluorescence antigenic mapping studies demonstrated tissue separation within or just above the level of the lamina lucida. Northern hybridization of keratinocyte mRNA revealed markedly reduced levels of the laminin beta-3 chain mRNA. Both unaffected parents were shown to be heterozygous carriers. Ashton et al. (1997) assessed the frequency of the R635X mutation in 12 British patients with lethal (Herlitz) junctional EB using PCR amplification of genomic DNA and restriction endonuclease digestion. R635X was found in 7 of 24 (29%) mutant alleles, confirming its relative frequency within the British gene pool. In addition, haplotype analysis using intragenic polymorphisms showed that the mutation arose on at least 4 different haplotype backgrounds, suggesting that it represents a mutation hotspot rather than propagation of a common British ancestral allele. These findings supported the hypermutable nature of this CpG dinucleotide. In studies of a European cohort of 14 families with the lethal Herlitz type of junctional EB, Pulkkinen et al. (1997) found the R635X mutation in the homozygous state in 4 of the probands and in the heterozygous state in 6 of the probands. In all, LAMB3 mutations accounted for 22 (79%) of 28 junctional EB alleles, and 14 (64%) of 22 LAMB3 alleles harbored the R635X mutation. In a study of 12 patients with Herlitz junctional EB, Muhle et al. (2005) observed that the 4 patients who survived longer than 6 months were females who were homozygous for R635X. In these 4 patients, disease progression as quantified by the percentage of affected body surface occurred relatively slowly during the first months of life, and they had better initial development and weight gain. However, they all died between 7.5 and 30 months of age. The 1 male patient who was also homozygous for R635X presented with a large skin defect at birth and remained hospitalized because of severe chronic wound infections and failure to thrive until his death at 5 months of age. Muhle et al. (2005) concluded that modifying factors may lead to significant variability in the clinical course of the disease and that other diagnostic means such as immunofluorescence and mRNA analysis should be taken into account when assessing the prognosis of an individual patient. Intermediate Junctional Epidermolysis Bullosa 1A In 2 sibs with nonlethal JEB (JEB1A; 226650), Pulkkinen and Uitto (1998) detected compound heterozygosity for premature termination mutations in LAMB3, the recurrent R235X mutation on the maternal allele and a 5-basepair deletion (1438del5; 150310.0010) on the paternal allele. The 1438del5 mutation resulted in a premature termination codon 164 nucleotides downstream from the deletion in exon 14. This report represented the first exception to the general rule that mutations leading to premature termination codons on both alleles result in Herlitz (lethal) JEB, whereas in nonlethal variants at least one allele has a missense or in-frame exon skip mutation. Floeth and Bruckner-Tuderman (1999) described a family with severe nonlethal junctional EB (JEB1A) who had mutations in both the LAMB3 and type XVII collagen (COL17A1; 113811) genes. The index patient was compound heterozygous for 2 mutations in the COL17A1 gene, L855X (113811.0012) and R1226X (113811.0001), and was heterozygous for the R635X mutation in the LAMB3 gene. As a consequence, 2 functionally related proteins were affected. Absence of collagen XVII and attenuated laminin-5 expression resulted in rudimentary hemidesmosome structure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heterozygotes in this family carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathologic skin phenotype. These observations indicated that the known allelic heterogeneity in junctional EB is further complicated by interactions between unlinked mutations. They also demonstrated that identification of 1 mutation in 1 gene is not sufficient for determination of the genetic basis of junctional EB in a given family. (less)
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Pathogenic
(Jan 01, 2005)
|
no assertion criteria provided
Method: literature only
|
EPIDERMOLYSIS BULLOSA, JUNCTIONAL 1B, SEVERE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035903.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2024 |
Comment on evidence:
Severe Junctional Epidermolysis Bullosa 1B In an infant with the Herlitz form of junctional epidermolysis bullosa (JEB1B; 226700), Pulkkinen et al. (1994) identified a homozygous … (more)
Severe Junctional Epidermolysis Bullosa 1B In an infant with the Herlitz form of junctional epidermolysis bullosa (JEB1B; 226700), Pulkkinen et al. (1994) identified a homozygous C-to-T transition in the LAMB3 gene, resulting in an arg635-to-ter (R635X) substitution. Ultrastructural and immunofluorescence antigenic mapping studies demonstrated tissue separation within or just above the level of the lamina lucida. Northern hybridization of keratinocyte mRNA revealed markedly reduced levels of the laminin beta-3 chain mRNA. Both unaffected parents were shown to be heterozygous carriers. Ashton et al. (1997) assessed the frequency of the R635X mutation in 12 British patients with lethal (Herlitz) junctional EB using PCR amplification of genomic DNA and restriction endonuclease digestion. R635X was found in 7 of 24 (29%) mutant alleles, confirming its relative frequency within the British gene pool. In addition, haplotype analysis using intragenic polymorphisms showed that the mutation arose on at least 4 different haplotype backgrounds, suggesting that it represents a mutation hotspot rather than propagation of a common British ancestral allele. These findings supported the hypermutable nature of this CpG dinucleotide. In studies of a European cohort of 14 families with the lethal Herlitz type of junctional EB, Pulkkinen et al. (1997) found the R635X mutation in the homozygous state in 4 of the probands and in the heterozygous state in 6 of the probands. In all, LAMB3 mutations accounted for 22 (79%) of 28 junctional EB alleles, and 14 (64%) of 22 LAMB3 alleles harbored the R635X mutation. In a study of 12 patients with Herlitz junctional EB, Muhle et al. (2005) observed that the 4 patients who survived longer than 6 months were females who were homozygous for R635X. In these 4 patients, disease progression as quantified by the percentage of affected body surface occurred relatively slowly during the first months of life, and they had better initial development and weight gain. However, they all died between 7.5 and 30 months of age. The 1 male patient who was also homozygous for R635X presented with a large skin defect at birth and remained hospitalized because of severe chronic wound infections and failure to thrive until his death at 5 months of age. Muhle et al. (2005) concluded that modifying factors may lead to significant variability in the clinical course of the disease and that other diagnostic means such as immunofluorescence and mRNA analysis should be taken into account when assessing the prognosis of an individual patient. Intermediate Junctional Epidermolysis Bullosa 1A In 2 sibs with nonlethal JEB (JEB1A; 226650), Pulkkinen and Uitto (1998) detected compound heterozygosity for premature termination mutations in LAMB3, the recurrent R235X mutation on the maternal allele and a 5-basepair deletion (1438del5; 150310.0010) on the paternal allele. The 1438del5 mutation resulted in a premature termination codon 164 nucleotides downstream from the deletion in exon 14. This report represented the first exception to the general rule that mutations leading to premature termination codons on both alleles result in Herlitz (lethal) JEB, whereas in nonlethal variants at least one allele has a missense or in-frame exon skip mutation. Floeth and Bruckner-Tuderman (1999) described a family with severe nonlethal junctional EB (JEB1A) who had mutations in both the LAMB3 and type XVII collagen (COL17A1; 113811) genes. The index patient was compound heterozygous for 2 mutations in the COL17A1 gene, L855X (113811.0012) and R1226X (113811.0001), and was heterozygous for the R635X mutation in the LAMB3 gene. As a consequence, 2 functionally related proteins were affected. Absence of collagen XVII and attenuated laminin-5 expression resulted in rudimentary hemidesmosome structure and separation of the epidermis from the basement membrane, with severe skin blistering as the clinical manifestation. In contrast, single heterozygotes in this family carrying either (1) one or the other of the COL17A1 null alleles or (2) a double heterozygote for a COL17A1 and a LAMB3 null allele did not have a pathologic skin phenotype. These observations indicated that the known allelic heterogeneity in junctional EB is further complicated by interactions between unlinked mutations. They also demonstrated that identification of 1 mutation in 1 gene is not sufficient for determination of the genetic basis of junctional EB in a given family. (less)
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Pathogenic
(Dec 21, 2023)
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no assertion criteria provided
Method: clinical testing
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LAMB3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004772093.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
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, … (more)
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. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001930983.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001972525.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Junctional epidermolysis bullosa gravis of Herlitz
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000040565.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Junctional Epidermolysis Bullosa. | Adam MP | - | 2018 | PMID: 20301304 |
| Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications. | Vahidnezhad H | The Journal of investigative dermatology | 2017 | PMID: 28830826 |
| A unique LAMB3 splice-site mutation with founder effect from the Balkans causes lethal epidermolysis bullosa in several European countries. | Mayer B | The British journal of dermatology | 2016 | PMID: 27062385 |
| Junctional epidermolysis bullosa with LAMB3 splice-site mutations. | Kiritsi D | Acta dermato-venereologica | 2015 | PMID: 25708563 |
| Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands. | Yuen WY | The British journal of dermatology | 2011 | PMID: 21801158 |
| Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3. | Pasmooij AM | The Journal of clinical investigation | 2007 | PMID: 17476356 |
| Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants. | Varki R | Journal of medical genetics | 2006 | PMID: 16473856 |
| Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa. | Fassihi H | Clinical and experimental dermatology | 2005 | PMID: 15663509 |
| Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease. | Mühle C | Human genetics | 2005 | PMID: 15538630 |
| Analysis of the LAMB3 gene in a junctional epidermolysis bullosa patient reveals exonic splicing and allele-specific nonsense-mediated mRNA decay. | Buchroithner B | Laboratory investigation; a journal of technical methods and pathology | 2004 | PMID: 15311214 |
| Genetic bases of severe junctional epidermolysis bullosa presenting spontaneous amelioration with aging. | Gache Y | Human molecular genetics | 2001 | PMID: 11689492 |
| Junctional epidermolysis bullosa gravis (Herlitz): diagnostic and genetic aspects. | Hauschild R | Journal of the European Academy of Dermatology and Venereology : JEADV | 2001 | PMID: 11451332 |
| DNA based molecular analysis in the rapid diagnosis of Herlitz junctional epidermolysis bullosa. | Cserhalmi-Friedman PB | Clinical and experimental dermatology | 2001 | PMID: 11298117 |
| Herlitz junctional epidermolysis bullosa: novel and recurrent mutations in the LAMB3 gene and the population carrier frequency. | Nakano A | The Journal of investigative dermatology | 2000 | PMID: 11023379 |
| Digenic junctional epidermolysis bullosa: mutations in COL17A1 and LAMB3 genes. | Floeth M | American journal of human genetics | 1999 | PMID: 10577906 |
| Heterozygosity for premature termination codon mutations in LAMB3 in siblings with non-lethal junctional epidermolysis bullosa. | Pulkkinen L | The Journal of investigative dermatology | 1998 | PMID: 9856855 |
| Predominance of the recurrent mutation R635X in the LAMB3 gene in European patients with Herlitz junctional epidermolysis bullosa has implications for mutation detection strategy. | Pulkkinen L | The Journal of investigative dermatology | 1997 | PMID: 9242513 |
| A recurrent laminin 5 mutation in British patients with lethal (Herlitz) junctional epidermolysis bullosa: evidence for a mutational hotspot rather than propagation of an ancestral allele. | Ashton GH | The British journal of dermatology | 1997 | PMID: 9205497 |
| Molecular complexity of the cutaneous basement membrane zone. | Uitto J | Molecular biology reports | 1996 | PMID: 8983017 |
| Mutational hotspots in the LAMB3 gene in the lethal (Herlitz) type of junctional epidermolysis bullosa. | Kivirikko S | Human molecular genetics | 1996 | PMID: 8824879 |
| A homozygous nonsense mutation in the beta 3 chain gene of laminin 5 (LAMB3) in Herlitz junctional epidermolysis bullosa. | Pulkkinen L | Genomics | 1994 | PMID: 7698759 |
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Text-mined citations for rs80356682 ...
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Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.