chr8-143924012-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_201384.3(PLEC):c.5917C>T(p.Arg1973Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,588,138 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1973Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_201384.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLEC | NM_201384.3 | c.5917C>T | p.Arg1973Trp | missense_variant | 31/32 | ENST00000345136.8 | |
PLEC | NM_201378.4 | c.5875C>T | p.Arg1959Trp | missense_variant | 31/32 | ENST00000356346.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLEC | ENST00000345136.8 | c.5917C>T | p.Arg1973Trp | missense_variant | 31/32 | 1 | NM_201384.3 | ||
PLEC | ENST00000356346.7 | c.5875C>T | p.Arg1959Trp | missense_variant | 31/32 | 1 | NM_201378.4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 36
GnomAD4 exome AF: 0.00000279 AC: 4AN: 1435988Hom.: 0 Cov.: 74 AF XY: 0.00000280 AC XY: 2AN XY: 714096
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152150Hom.: 0 Cov.: 36 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Epidermolysis bullosa simplex, Ogna type Pathogenic:3Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jul 07, 2023 | This sequence change in PLEC is predicted to replace arginine with tryptophan at codon 1973, p.(Arg1973Trp) (also known as p.Arg1999Trp, p.Arg2000Trp, p.Arg2110Trp). The arginine residue is moderately conserved (73/91 vertebrates, UCSC), and is located in the central fibrous rod domain. There is a large physicochemical difference between arginine and tryptophan. This variant is absent from the population database gnomAD v2.1 and present in a single Latino/Admixed American individual in gnomAD v3.1 (1/15,270 alleles). This variant was identified in the original epidermolysis bullosa simplex Ogna (EBS-Ogna) type Norwegian family segregating with disease and has been reported in multiple other affected families with evidence of co-segregation (PMID: 11851880, 23774525). This variant has been identified as a de novo occurrence with confirmed parental relationships in at least one individual with EBS-Ogna (PMID: 11851880). A knock-in mouse model of the variant recapitulates the human EBS-Ogna phenotype, including the development of microlesions and skin fragility (PMID: 22144912). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.689). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2, PP1_Strong, PS3_Moderate, PS4_Supporting, PM2_Supporting, PP3. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | - | The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.01). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008262 / PMID: 11851880). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11851880, 22854623, 29453417). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11851880, 22854623). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
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
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 8262). This variant is also known as R2110W. This missense change has been observed in individuals with clinical features of autosomal dominant epidermolysis bullosa (PMID: 11851880, 22854623, 29453417). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2000 of the PLEC protein (p.Arg2000Trp). - |
Simplex epidermolysis bullosa_Ogna type Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Mar 21, 2016 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 12, 2022 | Published functional studies demonstrate that the R2000W variant renders the PLEC protein's coiled-coil domain vulnerable to cleavage by calpains and other proteases in the epidermis; treatment with calpain inhibitors resulted in increased PLEC protein levels (Walko et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; This variant is associated with the following publications: (PMID: 22854623, 23774525, 31001817, 11851880, 22144912, 29453417, 22864774) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at