ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.1381C>G (p.Leu461Val) (rs121913016)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000897210 SCV001041336 benign not provided 2019-12-31 criteria provided, single submitter clinical testing
Mendelics RCV000018267 SCV001141103 uncertain significance Xeroderma pigmentosum, group D 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000897210 SCV001151955 uncertain significance not provided 2021-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000018267 SCV001368068 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.
GeneDx RCV000897210 SCV001874817 uncertain significance not provided 2021-07-16 criteria provided, single submitter clinical testing Published functional studies of the A717G;L461V complex allele demonstrated a reduced TFIIH binding capacity with partial NER activity compared to wild-type, but no functional data for Leu461Val on its own exist (Horibata et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26556299, 31980526, 7585650, 9195225, 23221806, 25716912, 26884178, 30136158, 29607586, 27504877, 18470933, 12820975, 16135823, 12393803, 10064601, 7849702, 15982307, 9238033, 19681155, 23232694, 10447254, 12116233, 8571952, 22234153, 24728327)
OMIM RCV000018267 SCV000038546 pathogenic Xeroderma pigmentosum, group D 1997-01-01 no assertion criteria provided literature only
ITMI RCV000120764 SCV000084928 not provided not specified 2013-09-19 no assertion provided reference population
OMIM RCV000171546 SCV000223722 pathogenic Trichothiodystrophy 1, photosensitive 1997-01-01 no assertion criteria provided literature only
Reproductive Health Research and Development,BGI Genomics RCV000018267 SCV001142492 uncertain significance Xeroderma pigmentosum, group D 2020-01-06 no assertion criteria provided curation NM_000400.3:c.1381C>G in the ERCC2 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. The functional study (GM436 cells) demenstrated Leu461Val exits in apparent absence of expression of the other XPD allele. Hence, the Leu461Val allele can be assumed not to interfere with the essential function of the XPD (ERCC2) gene product (PMID: 7849702). Takayama et al reported a patient with typical trichothiodystrophy characteristics, harboring Leu461Val and a deletion of amino acids 716-730 in one allele and Ala725Pro in the other allele; the pathogenicity of Ala725Pro, however, is not determined (PMID: 9195225). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PP3.

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