Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Baylor Genetics | RCV001331198 | SCV001523183 | uncertain significance | Trichothiodystrophy 1, photosensitive | 2020-01-07 | criteria provided, single submitter | clinical testing | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. |
| Invitae | RCV001871815 | SCV002274776 | uncertain significance | not provided | 2022-02-18 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 7 of the ERCC2 gene. It does not directly change the encoded amino acid sequence of the ERCC2 protein. This variant is present in population databases (rs761737358, gnomAD 0.003%). This variant has been observed in individual(s) with xeroderma pigmentosum (PMID: 18470933). ClinVar contains an entry for this variant (Variation ID: 1029821). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387999 | SCV004099833 | likely pathogenic | Xeroderma pigmentosum | 2023-09-14 | criteria provided, single submitter | clinical testing | Variant summary: ERCC2 c.595-10G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 3' acceptor site and two predict the variant weakens a 3' acceptor site. Additionally, three tools predict the variant creates a 3' acceptor site 8 nucleotides upstream, potentially leading to a frameshift. At least one publication reports experimental evidence that this variant affects mRNA splicing, supporting computational predictions, and finding that the variant results in an 8-nt insertion causing a frameshift (p.I199Pfs*52; Boyle_2008, Ueda_2009). The variant allele was found at a frequency of 8.1e-06 in 247614 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.595-10G>A has been reported in the literature in at least two compound heterozygous siblings affected with Xeroderma Pigmentosum (e.g., Boyle_2008, Ueda_2009). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant severely disrupts nucleotide excision repair activity, p44-XPD interaction, basal transcription, and several other protein functions (e.g., Ueda_2009). The following publications have been ascertained in the context of this evaluation (PMID: 18470933, 19934020). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |