rs1057517096
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000228.3(LAMB3):c.1117C>T(p.Gln373Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,856 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q373Q) 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.1117C>T | p.Gln373Ter | stop_gained | 10/23 | ENST00000356082.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.1117C>T | p.Gln373Ter | stop_gained | 10/23 | 1 | NM_000228.3 | P1 | |
LAMB3 | ENST00000367030.7 | c.1117C>T | p.Gln373Ter | stop_gained | 10/23 | 1 | P1 | ||
LAMB3 | ENST00000391911.5 | c.1117C>T | p.Gln373Ter | stop_gained | 9/22 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251412Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135896
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461856Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727230
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22931927, 11023379, 25950805, 15538630, 28830826) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 17, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371216). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 11023379, 25950805, 28830826). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln373*) 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). - |
Junctional epidermolysis bullosa, non-Herlitz type Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Pars Genome Lab | - | - - |
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Junctional epidermolysis bullosa Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Oct 30, 2018 | The LAMB3 c.1117C>T (p.Gln373Ter) variant is a stop-gained variant predicted to result in premature termination of the protein. It has been reported in two studies in which is found in a compound heterozygous state with the recurrent LAMB3 variant, p.Arg635Ter, in three affected individuals. All three individuals presented with a severe, neonatal-lethal form of junctional epidermolysis bullosa known as Herlitz disease or H-JEB. (Muhle et al. 2005; Tolar et al. 2013) Control data are unavailable for this variant, which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage, so the variant is presumed to be rare. Skin biopsy studies showed reduced laminin-5 expression in two probands (Muhle et al. 2005) and absence of laminin B3 chain at the dermal epidermal junction in one proband (Tolar et al. 2013). Based on the evidence, the variant is classified as likely 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