ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.594+2_594+5del (rs762309206)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454337 SCV000538021 likely pathogenic Trichothiodystrophy 1, photosensitive 2015-12-04 criteria provided, single submitter clinical testing The c.594+2_594+5delTGAG splice-donor variant in the ERCC2 gene has not been previously reported. There has been a splice-donor variant in intron 7 of the ERCC2 gene observed in one affected individual with Trichothiodystrophy and was predicted to be a null allele. The affected individual was heterozygous for the splice-donor variant but also harbored a missense variant of unknown significance in the ERCC2 gene (Viprakasit et al., 2001). Although missense variants are a common mechanism for disease, loss of function variants have been reported in individuals affected with Xeroderma Pigmentosum. The c.594+2_594+5delTGAG splice-donor variant is present at a very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc). Computational algorithms predict evolutionary conservation at this locus and a loss of the splice-donor site resulting in intron retention and introduction of a premature termination codon. In summary, this collective evidence supports the provisional classification of the c.594+2_594+5delTGAG variant as Likely Pathogenic
Eurofins NTD, LLC RCV000599593 SCV000704022 likely pathogenic not provided 2016-11-30 criteria provided, single submitter clinical testing
GeneDx RCV000599593 SCV000709929 pathogenic not provided 2021-12-02 criteria provided, single submitter clinical testing Canonical splice site variant predicted to result in an in-frame deletion of a critical region; Observed in trans with a second ERCC2 variant in an individual with trichothiodystrophy (Viprakasit 2001); Published functional studies demonstrate abnormal splicing (Punj 2018); This variant is associated with the following publications: (PMID: 29754767, 31589614, 11734544)
CeGaT Praxis fuer Humangenetik Tuebingen RCV000599593 SCV001151956 likely pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
Invitae RCV000599593 SCV001574605 likely pathogenic not provided 2017-11-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the ERCC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs762309206, ExAC 0.01%). This variant has been reported in an individual affected with trichothiodystrophy (PMID: 11734544). ClinVar contains an entry for this variant (Variation ID: 402226). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ERCC2 are known to be pathogenic (PMID: 9238033, 11335038, 19085937, 19934020). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 1
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000454224 SCV000538022 likely pathogenic Xeroderma pigmentosum, group D 2015-12-04 no assertion criteria provided clinical testing

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