NM_201384.3:c.6874C>T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_201384.3(PLEC):c.6874C>T(p.Arg2292*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,458,394 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_201384.3 stop_gained
Scores
Clinical Significance
Conservation
Publications
- epidermolysis bullosa simplexInheritance: AD Classification: STRONG Submitted by: G2P
- epidermolysis bullosa simplex 5A, Ogna typeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
- autosomal recessive limb-girdle muscular dystrophy type 2QInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- congenital myasthenic syndromeInheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
- epidermolysis bullosa simplex 5B, with muscular dystrophyInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
- epidermolysis bullosa simplex 5C, with pyloric atresiaInheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- epidermolysis bullosa simplex with nail dystrophyInheritance: AR Classification: STRONG Submitted by: PanelApp Australia
- autosomal recessive limb-girdle muscular dystrophyInheritance: AR Classification: MODERATE Submitted by: ClinGen
- aplasia cutis congenitaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- cholestasisInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.6874C>T | p.Arg2292* | stop_gained | Exon 31 of 32 | 1 | NM_201384.3 | ENSP00000344848.3 | ||
PLEC | ENST00000356346.7 | c.6832C>T | p.Arg2278* | stop_gained | Exon 31 of 32 | 1 | NM_201378.4 | ENSP00000348702.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD2 exomes AF: 0.0000207 AC: 5AN: 241484 AF XY: 0.0000302 show subpopulations
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1458394Hom.: 0 Cov.: 70 AF XY: 0.0000179 AC XY: 13AN XY: 725634 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
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The R2319X variant in the PLEC gene has been reported previously in the homozygous or compound heterozygous state in multiple individuals with epidermolysis bullosa (EB) with muscular dystrophy (EBS-MD) and also in one patient with EBS-MD and myasthenic syndrome (Takahashi et al., 2005; Yin et al., 2015; Vahidnezhad et al., 2017; Selcen et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R2319X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R2319X as a pathogenic variant. -
Epidermolysis bullosa simplex with nail dystrophy Pathogenic:1
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Epidermolysis bullosa simplex, Ogna type;C2677349:Epidermolysis bullosa simplex 5C, with pyloric atresia;C2931072:Epidermolysis bullosa simplex 5B, with muscular dystrophy;C3150989:Autosomal recessive limb-girdle muscular dystrophy type 2Q;C4225309:Epidermolysis bullosa simplex with nail dystrophy Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg2319*) in the PLEC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PLEC are known to be pathogenic (PMID: 20301336, 20447487, 21109228, 23289980, 28824526). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 30174). This premature translational stop signal has been observed in individuals with autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (PMID: 15659326, 28830826). This variant is present in population databases (rs387906802, gnomAD 0.007%). -
Epidermolysis bullosa simplex 5B, with muscular dystrophy Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at