NM_001290285.1(ERCC8):c.-83_-81delinsTG AND not provided

Clinical significance:Pathogenic (Last evaluated: Aug 30, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000493563.3

Allele description [Variation Report for NM_001290285.1(ERCC8):c.-83_-81delinsTG]

NM_001290285.1(ERCC8):c.-83_-81delinsTG

Genes:
ERCC8:ERCC excision repair 8, CSA ubiquitin ligase complex subunit [Gene - OMIM - HGNC]
ERCC8-AS1:ERCC8 antisense RNA 1 [Gene - HGNC]
Variant type:
Indel
Cytogenetic location:
5q12.1
Genomic location:
Preferred name:
NM_001290285.1(ERCC8):c.-83_-81delinsTG
HGVS:
  • NC_000005.10:g.60918367_60918369delinsCA
  • NG_009289.1:g.31710_31712delinsTG
  • NM_001007233.2:c.121_123delinsTG
  • NM_001007234.3:c.295_297delinsTG
  • NM_001290285.1:c.-83_-81delinsTG
  • NP_001007234.1:p.Arg41fs
  • NP_001007235.1:p.Arg99fs
  • LRG_466t1:c.295_297delAGAinsTG
  • LRG_466:g.31710_31712delinsTG
  • LRG_466p1:p.Arg99fs
  • NC_000005.9:g.60214194_60214196delinsCA
  • NM_000082.3:c.295_297delAGAinsTG
Protein change:
R41fs
Links:
dbSNP: rs1131691783
NCBI 1000 Genomes Browser:
rs1131691783
Molecular consequence:
  • NM_001290285.1:c.-83_-81delinsTG - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001007233.2:c.121_123delinsTG - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001007234.3:c.295_297delinsTG - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000582828GeneDxcriteria provided, single submitter
Pathogenic
(May 19, 2017)
germlineclinical testing

Citation Link,

SCV000936383Invitaecriteria provided, single submitter
Pathogenic
(Aug 30, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly.

Rump P, Jazayeri O, van Dijk-Bos KK, Johansson LF, van Essen AJ, Verheij JB, Veenstra-Knol HE, Redeker EJ, Mannens MM, Swertz MA, Alizadeh BZ, van Ravenswaaij-Arts CM, Sinke RJ, Sikkema-Raddatz B.

BMC Med Genomics. 2016 Feb 4;9:7. doi: 10.1186/s12920-016-0167-8.

PubMed [citation]
PMID:
26846091
PMCID:
PMC4743197

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From GeneDx, SCV000582828.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The c.295_297delAGAinsTG variant in the ERCC8 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.295_297delAGAinsTG variant causes a frameshift starting with codon Arginine 99, changes this amino acid to a Cysteine residue, and creates a premature Stop codon at position 26 of the new reading frame, denoted p.Arg99CysfsX26. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.295_297delAGAinsTG variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.295_297delAGAinsTG as a pathogenic variant.

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

From Invitae, SCV000936383.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Arg99Serfs*26) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with Cockayne syndrome type A (PMID: 26846091). ClinVar contains an entry for this variant (Variation ID: 430102). Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 19894250, 21108394). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2021

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