ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.2150C>G (p.Ala717Gly) (rs144564120)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255243 SCV000322086 pathogenic not provided 2021-06-28 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect, specifically, RNA studies suggest the missense variant creates a cryptic splice donor site upstream of the natural splice site, leading to an in-frame deletion of 15 amino acids (Takayama et al., 1995), and the A717G;L461V complex allele demonstrated a reduced TFIIH binding capacity with partial NER activity, as compared to wild-type (Horibata et al., 2015); Reported in multiple unrelated individuals on the same allele (in cis) with the L461V variant of uncertain significance (Takayama et al., 1995; Takayama et al., 1997; Orioli et al., 2013; Horibata et al., 2015; Fassihi et al. 2016); This variant is associated with the following publications: (PMID: 31589614, 23221806, 25716912, 26884178, 7585650, 9195225, 31980526, 30676620, 29607586, 27504877, 24728327, 22234153, 17020410, 15982307, 16135823, 8571952, 23232694)
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 2021-08-01 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

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