NM_201384.3:c.6874C>T

Variant names:

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

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PLEC
NM_201384.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.86

Publications

11 publications found

Variant links:

Genes affected

PLEC (HGNC:9069): (plectin) Plectin is a prominent member of an important family of structurally and in part functionally related proteins, termed plakins or cytolinkers, that are capable of interlinking different elements of the cytoskeleton. Plakins, with their multi-domain structure and enormous size, not only play crucial roles in maintaining cell and tissue integrity and orchestrating dynamic changes in cytoarchitecture and cell shape, but also serve as scaffolding platforms for the assembly, positioning, and regulation of signaling complexes (reviewed in PMID: 9701547, 11854008, and 17499243). Plectin is expressed as several protein isoforms in a wide range of cell types and tissues from a single gene located on chromosome 8 in humans (PMID: 8633055, 8698233). Until 2010, this locus was named plectin 1 (symbol PLEC1 in human; Plec1 in mouse and rat) and the gene product had been referred to as "hemidesmosomal protein 1" or "plectin 1, intermediate filament binding 500kDa". These names were superseded by plectin. The plectin gene locus in mouse on chromosome 15 has been analyzed in detail (PMID: 10556294, 14559777), revealing a genomic exon-intron organization with well over 40 exons spanning over 62 kb and an unusual 5' transcript complexity of plectin isoforms. Eleven exons (1-1j) have been identified that alternatively splice directly into a common exon 2 which is the first exon to encode plectin's highly conserved actin binding domain (ABD). Three additional exons (-1, 0a, and 0) splice into an alternative first coding exon (1c), and two additional exons (2alpha and 3alpha) are optionally spliced within the exons encoding the acting binding domain (exons 2-8). Analysis of the human locus has identified eight of the eleven alternative 5' exons found in mouse and rat (PMID: 14672974); exons 1i, 1j and 1h have not been confirmed in human. Furthermore, isoforms lacking the central rod domain encoded by exon 31 have been detected in mouse (PMID:10556294), rat (PMID: 9177781), and human (PMID: 11441066, 10780662, 20052759). The short alternative amino-terminal sequences encoded by the different first exons direct the targeting of the various isoforms to distinct subcellular locations (PMID: 14559777). As the expression of specific plectin isoforms was found to be dependent on cell type (tissue) and stage of development (PMID: 10556294, 12542521, 17389230) it appears that each cell type (tissue) contains a unique set (proportion and composition) of plectin isoforms, as if custom-made for specific requirements of the particular cells. Concordantly, individual isoforms were found to carry out distinct and specific functions (PMID: 14559777, 12542521, 18541706). In 1996, a number of groups reported that patients suffering from epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) lacked plectin expression in skin and muscle tissues due to defects in the plectin gene (PMID: 8698233, 8941634, 8636409, 8894687, 8696340). Two other subtypes of plectin-related EBS have been described: EBS-pyloric atresia (PA) and EBS-Ogna. For reviews of plectin-related diseases see PMID: 15810881, 19945614. Mutations in the plectin gene related to human diseases should be named based on the position in NM_000445 (variant 1, isoform 1c), unless the mutation is located within one of the other alternative first exons, in which case the position in the respective Reference Sequence should be used. [provided by RefSeq, Aug 2011]

PLEC Gene-Disease associations (from GenCC):

epidermolysis bullosa simplex
Inheritance: AD Classification: STRONG Submitted by: G2P
epidermolysis bullosa simplex 5A, Ogna type
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp
autosomal recessive limb-girdle muscular dystrophy type 2Q
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
congenital myasthenic syndrome
Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
epidermolysis bullosa simplex 5B, with muscular dystrophy
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Genomics England PanelApp
epidermolysis bullosa simplex 5C, with pyloric atresia
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
epidermolysis bullosa simplex with nail dystrophy
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
aplasia cutis congenita
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cholestasis
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

PLEC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 8-143923055-G-A is Pathogenic according to our data. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143923055-G-A is described in CliVar as Pathogenic. Clinvar id is 30174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLEC	NM_201384.3 link	c.6874C>T	p.Arg2292*	stop_gained	Exon 31 of 32	ENST00000345136.8	NP_958786.1	Q15149-4
PLEC	NM_201378.4 link	c.6832C>T	p.Arg2278*	stop_gained	Exon 31 of 32	ENST00000356346.7	NP_958780.1	Q15149-9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLEC	ENST00000345136.8 link	c.6874C>T	p.Arg2292*	stop_gained	Exon 31 of 32	1	NM_201384.3	ENSP00000344848.3		Q15149-4
PLEC	ENST00000356346.7 link	c.6832C>T	p.Arg2278*	stop_gained	Exon 31 of 32	1	NM_201378.4	ENSP00000348702.3		Q15149-9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000207

AC:

AN:

241484

AF XY:

0.0000302

show subpopulations

Gnomad AFR exome

AF:

0.0000697

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000561

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000275

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1458394

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

725634

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

1111730

Other (OTH)

AF:

0.00

AC:

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000497

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2019

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 25, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 25, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.93

PhyloP100

2.9

Vest4

0.84

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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