rs80356680
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000228.3(LAMB3):c.124C>T(p.Arg42Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,058 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000089 ( 0 hom. )
Consequence
LAMB3
NM_000228.3 stop_gained
NM_000228.3 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 2.40
Genes affected
LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]
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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 1-209650023-G-A is Pathogenic according to our data. Variant chr1-209650023-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-209650023-G-A is described in Lovd as [Pathogenic]. Variant chr1-209650023-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| LAMB3 | NM_000228.3 | c.124C>T | p.Arg42Ter | stop_gained | 3/23 | ENST00000356082.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| LAMB3 | ENST00000356082.9 | c.124C>T | p.Arg42Ter | stop_gained | 3/23 | 1 | NM_000228.3 | P1 | |
| LAMB3 | ENST00000367030.7 | c.124C>T | p.Arg42Ter | stop_gained | 3/23 | 1 | P1 | ||
| LAMB3 | ENST00000391911.5 | c.124C>T | p.Arg42Ter | stop_gained | 2/22 | 1 | P1 | ||
| LAMB3 | ENST00000415782.1 | c.124C>T | p.Arg42Ter | stop_gained | 3/6 | 2 |
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152182Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251436Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135892
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GnomAD4 exome AF: 0.0000889 AC: 130AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.000100 AC XY: 73AN XY: 727244
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GnomAD4 genome 0.0000591 AC: 9AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74344
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This sequence change creates a premature translational stop signal (p.Arg42*) 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 (rs80356680, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with autosomal recessive junctional epidermolysis bullosa (PMID: 7706760, 8824879, 8983017, 30544381). ClinVar contains an entry for this variant (Variation ID: 14541). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 31, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 17, 2022 | 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: 30544381, 25525159, 8824879, 7706760, 9767254, 32484238, 31589614, 33274474) - |
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1998 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 20, 2019 | NM_000228.2(LAMB3):c.124C>T(R42*) is classified as pathogenic in the context of LAMB3-related Herlitz junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 11023379 and 8983017. Classification of NM_000228.2(LAMB3):c.124C>T(R42*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 07, 2019 | Variant summary: The variant, LAMB3 c.124C>T (p.Arg42X) 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 by our laboratory (eg. c.1903C>T (p.Arg635X), c.1978C>T(p.Arg660X)). The variant allele was found at a frequency of 4.7e-05 in 277176 control chromosomes (gnomAD) and has been reported in the literature as a mutational hot spot in multiple individuals affected with Junctional Epidermolysis Bullosa (JEB), where some of these patients, including 2 homozygotes, were affected by the most severe, Herlitz type JEB (Kivirkko 1996, Matsui 1998, Hammersen 2016), while others had less severe forms of JEB (e.g. Abu Sa'd 2006, McGrath 1995). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact of the variant, and demonstrated strongly decreased mRNA levels, and lack of the protein product, in samples from a homozygous patient (Matsui 1998). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Junctional epidermolysis bullosa gravis of Herlitz;C0268374:Junctional epidermolysis bullosa, non-Herlitz type;C4011403:Amelogenesis imperfecta type 1A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
LAMB3-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 02, 2024 | The LAMB3 c.124C>T variant is predicted to result in premature protein termination (p.Arg42*). This variant has been reported in the homozygous and compound heterozygous states in association with autosomal recessive LAMB3-related disorders (Rossi et al. 2021. PubMed ID: 33274474; Kivirikko et al. 1996. PubMed ID: 8824879). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in LAMB3 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at