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NM_177986.5(DSG4):c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA (p.Ile459fs) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 11, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003680573.2

Allele description [Variation Report for NM_177986.5(DSG4):c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA (p.Ile459fs)]

NM_177986.5(DSG4):c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA (p.Ile459fs)

Genes:
DSG1-AS1:DSG1 antisense RNA 1 [Gene - HGNC]
DSG4:desmoglein 4 [Gene - OMIM - HGNC]
Variant type:
Microsatellite
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_177986.5(DSG4):c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA (p.Ile459fs)
HGVS:
  • NC_000018.10:g.31400963_31400978AAG[2]TCAAAATATAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA[1]
  • NG_013040.1:g.29187_29202AAG[2]TCAAAATATAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA[1]
  • NM_001134453.3:c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA
  • NM_177986.5:c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATAMANE SELECT
  • NP_001127925.1:p.Ile459fs
  • NP_817123.1:p.Ile459fs
  • NC_000018.9:g.28980925_28980926insAAGAAGTCAAAATATAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAA
  • NC_000018.9:g.28980926_28980941AAG[2]TCAAAATATAGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA[1]
Protein change:
I459fs
Molecular consequence:
  • NM_001134453.3:c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_177986.5:c.1375_1376insGGCCGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGCGGATCACGAGGTNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAAAGAAGTCAAAATATA - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004414117Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 11, 2022) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

The impact of retrotransposons on human genome evolution.

Cordaux R, Batzer MA.

Nat Rev Genet. 2009 Oct;10(10):691-703. doi: 10.1038/nrg2640. Review.

PubMed [citation]
PMID:
19763152
PMCID:
PMC2884099

A mobile threat to genome stability: The impact of non-LTR retrotransposons upon the human genome.

Konkel MK, Batzer MA.

Semin Cancer Biol. 2010 Aug;20(4):211-21. doi: 10.1016/j.semcancer.2010.03.001. Epub 2010 Mar 20. Review.

PubMed [citation]
PMID:
20307669
PMCID:
PMC2925057
See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004414117.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Retrotransposon insertions including LINE1 (L1), Alu, and SVA (SINE-VNTR-Alu) have been reported to be disease-causing through disruption of either a coding region or splice site (PMID: 19763152, 20307669, 22406018) and loss-of-function variants in DSG4 are known to be pathogenic (PMID: 16439973, 16575393). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with DSG4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change inserts a large fragment of DNA, likely a transposable element, in exon 10 of the DSG4 gene (c.1375_1376ins?), causing a frameshift at codon 459 (p.Ile459fs). The exact size and sequence of the insertion cannot be determined by the current assay. However, the insertion is expected to result in an absent or disrupted protein product.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024