Variant summary: XPA c.555G>C (p.Gln185His) results in a non-conservative amino acid change located in the C-terminal domain (IPR022656) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. This variant also affects the last nucleotide of exon 4, and therefore could affect splicing: one computational tool predicts a significant impact on normal splicing, indicating that the variant abolishes a canonical 5' splicing donor site. Publications have reported experimental evidence confirming that this variant indeed affects mRNA splicing (e.g. Satokata_1992, States_1996, Nagel_2014).The variant allele was found at a frequency of 1.2e-05 in 247850 control chromosomes, exclusively within the European (non-Finnish) subpopulation (i.e. 3/112734 alleles) in the gnomAD database. c.555G>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Xeroderma pigmentosum, who were all of Caucasian ancestry, and generally had milder skin symptoms and absent or delayed-onset neurological disease (e.g. Satokata_1992, States_1996, States_1998). These data indicate that the variant is very likely to be associated with disease. Several publications reported experimental evidence evaluating the variant, and demonstrated that almost no correctly spliced mRNA was detected, and some mRNAs with in-frame insertions or deletions were also generated that theoretically could produce functional proteins (e.g. Satokata_1992, States_1996, Nagel_2014). This was consistent with a somewhat preserved UV-resistance of a patient-derived cell line that was homozygous for the variant of interest, and might also explain the milder clinical phenotypes reported in patients (Satokata_1992). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Both laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The XPA c.555G>C variant is predicted to result in the amino acid substitution p.Gln185His. This variant has been reported in the homozygous and compound heterozygous states in individuals with Xeroderma pigmentosum (Satokata et al. 1992. PubMed ID: 1372103; States et al. 1996. PubMed ID: 8765158). This variant is also at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. Functional studies showed that this variant affects XPA function (Satokata et al. 1992. PubMed ID: 1372103; States et al. 1996. PubMed ID: 8765158; Nagel et al. 2014. PubMed ID: 24757057). This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-100449378-C-G). This variant is interpreted as likely pathogenic.

This sequence change affects codon 185 of the XPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the XPA protein. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is present in population databases (rs746617574, gnomAD 0.003%). This variant has been observed in individual(s) with clinical features of XPA-related conditions (PMID: 1372103). ClinVar contains an entry for this variant (Variation ID: 550646). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this variant affects XPA function (PMID: 24757057). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 1372103). 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.

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