rs146794392
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000228.3(LAMB3):c.1978C>T(p.Arg660Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R660R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000228.3 stop_gained, splice_region
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.1978C>T | p.Arg660Ter | stop_gained, splice_region_variant | 15/23 | ENST00000356082.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMB3 | ENST00000356082.9 | c.1978C>T | p.Arg660Ter | stop_gained, splice_region_variant | 15/23 | 1 | NM_000228.3 | P1 | |
LAMB3 | ENST00000367030.7 | c.1978C>T | p.Arg660Ter | stop_gained, splice_region_variant | 15/23 | 1 | P1 | ||
LAMB3 | ENST00000391911.5 | c.1978C>T | p.Arg660Ter | stop_gained, splice_region_variant | 14/22 | 1 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152168Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000200 AC: 5AN: 249798Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135244
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1460208Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 726524
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74456
ClinVar
Submissions by phenotype
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 10, 2018 | Variant summary: LAMB3 c.1978C>T (p.Arg660X) 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. The variant allele was found at a frequency of 2.2e-05 in 275670 control chromosomes (gnomAD). c.1978C>T has been reported in the literature in multiple individuals affected with Junctional Epidermolysis Bullosa (Christiano_1997, Yuen_2011, Varki_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jun 30, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.Arg660*) 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 (rs146794392, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive junctional epidermolysis bullosa (PMID: 9160387, 21801158). ClinVar contains an entry for this variant (Variation ID: 189034). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 12, 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: 16473856, 12813757, 8824879, 21801158, 9160387) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at