ClinVar Miner

Submissions for variant NM_000400.3(ERCC2):c.2150C>G (p.Ala717Gly) (rs144564120)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255243 SCV000322086 pathogenic not provided 2018-09-13 criteria provided, single submitter clinical testing The c.2150C>G variant in the ERCC2 gene has been reported previously in multiple unrelated individuals with xeroderma pigmentosum (XP) or trichothiodystrophy (TTD), who harbored another variant on the opposite ERCC2 allele. The L461V variant of uncertain significance has also been present on the same ERCC2 allele (in cis) in every published report of the c.2150C>G variant (Takayama et al., 1995; Takayama et al., 1997; Zhou et al., 2013; Orioli et al., 2013). The c.2150C>G variant is observed in 88/277040 (0.03%) alleles in large population cohorts (Lek et al., 2016). The c.2150 C>G variant creates a cryptic donor splice site which results in an in-frame deletion of 15 amino acids (Takayama et al., 1995). Functional studies show that c.2150C>G may be able to partially rescue the UV hypersensitivity of an XPD-deficient cell line, suggesting that this variant leads to a milder phenotype (Horibata et al., 2015). We interpret c.2150 C>G as a pathogenic variant.
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761018 SCV000890933 likely pathogenic Mixed Phenotype Acute Leukemia, T/Myeloid, Not Otherwise Specified 2016-01-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000778547 SCV000914845 pathogenic ERCC2-Related Disorders 2019-01-09 criteria provided, single submitter clinical testing The ERCC2 c.2150C>G (p.Ala717Gly) variant creates a new splice donor site which results in altered splicing leading to a 15 amino acid deletion (p.Val716_Arg730del) (Takayama et al. 1995; Horibata et al. 2015). The p.Val716_Arg730del variant is described in at least six studies, in which it is always found in cis with a missense variant, c.1381C>G (p.Leu461Val), to give the complex allele: [c.1381C>G (p.Leu461Val); c.2150C>G (p.Val716_Arg730del)] (Takayama et al. 1995; Takayama et al. 1997; Moslehi et al. 2012; Orioli et al. 2013; Zhou et al. 2013; Horibata et al. 2015). The complex allele (p.Leu461Val; p.Val716_Arg730del) has been reported in a compound heterozygous state with another missense variant in a total of 16 individuals with either xeroderma pigmentosum (XP) or trichothiodystrophy. Orioli et al. (2013) report the (p.Leu461Val; p.Val716_Arg730del) allele in a compound heterozygous state with a missense variant in a patient with a severe XP phenotype. The patient had 48% of normal transcription factor TFIIH levels in fibroblasts and 10% of typical UV-induced DNA repair synthesis ability. Horibata et al. (2015) performed functional studies demonstrating that the (p.Leu461Val; p.Val716_Arg730del) allele was functionally null in nucleotide excision repair and not able to form the TFIIH complex. The p.Ala717Gly and p.Leu461Val variants in isolation performed similarly to wild type in nucleotide excision repair and were able to fully or partly form the TFIIH complex and rescue the UV hypersensitivity. Zhou et al. (2013) also showed that the (p.Leu461Val; p.Val716_Arg730del) allele exhibited decreased DNA repair. The p.Ala717Gly variant is reported at a frequency of 0.0005124 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the (p.Leu461Val; p.Val716_Arg730del) allele is classified as pathogenic for ERCC2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Mendelics RCV000990227 SCV001141100 pathogenic Xeroderma pigmentosum, group D 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255243 SCV001248923 pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000990227 SCV001368067 uncertain significance Xeroderma pigmentosum, group D 2019-05-13 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3,PP5.
Baylor Genetics RCV001329855 SCV001521404 pathogenic Trichothiodystrophy 1, photosensitive 2020-04-27 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000120774 SCV000084938 not provided not specified 2013-09-19 no assertion provided reference population

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.