rs80356683
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005562.3(LAMC2):c.283C>T(p.Arg95Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,836 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
Consequence
NM_005562.3 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 |
---|---|---|---|---|---|---|---|
LAMC2 | NM_005562.3 | c.283C>T | p.Arg95Ter | stop_gained | 3/23 | ENST00000264144.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LAMC2 | ENST00000264144.5 | c.283C>T | p.Arg95Ter | stop_gained | 3/23 | 1 | NM_005562.3 | P1 | |
LAMC2 | ENST00000493293.5 | c.283C>T | p.Arg95Ter | stop_gained | 3/22 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251448Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461836Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727212
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Epidermolysis bullosa, junctional 3B, severe Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 29, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Herlitz junctional epidermolysis bullosa (MIM#226700) and non-Herlitz junctional epidermolysis bullosa (MIM#226650). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a recurrent variant in patients with junctional epidermolysis bullosa, including in the homozygous state in at least two patient with Herlitz junctional epidermolysis bullosa (ClinVar, PMID: 17916201). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Junctional epidermolysis bullosa gravis of Herlitz Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 11, 2019 | NM_005562.2(LAMC2):c.283C>T(R95*) is classified as pathogenic in the context of LAMC2-related junctional epidermolysis bullosa. Sources cited for classification include the following: PMID 17916201, 9085255, 15373767, 8012394 and 8983017. Classification of NM_005562.2(LAMC2):c.283C>T(R95*) 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 | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 02, 2023 | ClinVar contains an entry for this variant (Variation ID: 14555). This premature translational stop signal has been observed in individual(s) with junctional epidermolysis bullosa (PMID: 8012394). This variant is present in population databases (rs80356683, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg95*) in the LAMC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LAMC2 are known to be pathogenic (PMID: 11907499, 16473856). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at