ClinVar Genomic variation as it relates to human health

The c.1479+2dupT variant is reported in one study in which it was found in two unrelated individuals with trichothiodystrophy who were both compound heterozygous for the c.1479+2dupT variant, one with a deletion variant on the second allele and one with a missense variant (Broughton et al. 1994). Both individuals displayed a DNA repair deficiency. Control data are not available for this variant, which is reported at a frequency of 0.00002 in the European (Non-Finnish) population of the Exome Aggregation Consortium database. This frequency is based on one allele only so the variant is presumed to be rare. RT-PCR studies showed an 18 bp deletion due to the c.1479+2dupT variant resulting in an in-frame loss of six amino acids in exon 15. Based on the limited evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for ERCC2-related disorders.

The c.1479+2dupT variant in ERCC2 has been reported in 2 individuals with Xerode rma pigmentosum, including in trans with a truncating allele in one individual ( Broughton 1994), and has been reported in ClinVar (Variation ID: 329511). The va riant has been identified in 2/110536 European chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs776705174). Pl ease note that for diseases with clinical variability, reduced penetrance, or re cessive inheritance, pathogenic variants may be present at a low frequency in th e general population. This variant occurs in the invariant region (+/- 1,2) of t he splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro data suggest this variant results in the deletion of 18 nucleotides, corresponding to an in-frame deletion. In summar y, although additional studies are required to fully establish its clinical sign ificance, the c.1479+2dupT variant is likely pathogenic. ACMG/AMP Criteria appli ed: PM2; PM3; PM4.

Canonical splice site variant expected to result in aberrant splicing. Functional studies have demonstrated two mRNA products are created; one with loss of exon 15 and another with an 18bp deletion due to use of a cryptic site (Broughton et al., 1994); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 7920640, 31980526)

Variant summary: ERCC2 c.1479+2dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site and one predicts the variant weakens the canonical 5' donor site. This variant has been found to affect mRNA splicing, resulting in loss of exon 15 or the last 18 nucleotides of exon 15 due to use of a cryptic splice site (Broughton_1994). The variant allele was found at a frequency of 4e-06 in 248778 control chromosomes (gnomAD). c.1479+2dupT has been reported in the literature in individuals affected with trichothiodystrophy (Broughton_1994). These data indicate that the variant may be associated with disease. Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

This sequence change falls in intron 15 of the ERCC2 gene. It does not directly change the encoded amino acid sequence of the ERCC2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs776705174, gnomAD 0.002%). This variant has been observed in individual(s) with trichothiodystrophy (PMID: 7920640). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as +T insertion in splice donor site of intron 15. ClinVar contains an entry for this variant (Variation ID: 329511). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The ERCC2 c.1479+2dupT variant is predicted to result in an intronic duplication. This variant was reported in the compound heterozygous state in two unrelated individuals with ERCC2-related disorders. RT-PCR studies derived from patients harboring this variant revealed two aberrant transcripts, one containing an 18bp deletion resulting in loss of amino acids 488-493 at the 3' end of exon 15 and another containing a 102bp deletion resulting in loss of amino acids 460-493 corresponding to exon 15 (described as +T insertion in the splice donor site of intron 15 in Broughton et al 1994. PubMed ID: 7920640). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.