Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001056570 | SCV001221020 | pathogenic | not provided | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change falls in intron 4 of the XPA gene. It does not directly change the encoded amino acid sequence of the XPA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs756967163, gnomAD 0.04%). This variant has been observed in individuals with xeroderma pigmentosum (PMID: 16792756, 26659639, 26743599, 26884178). ClinVar contains an entry for this variant (Variation ID: 852033). Studies have shown that this variant results in the activation of an alternative splice donor in intron 4 and introduces a premature termination codon (PMID: 16792756). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001585956 | SCV001821428 | pathogenic | Xeroderma pigmentosum | 2021-08-30 | criteria provided, single submitter | clinical testing | Variant summary: XPA c.555+8A>G alters a non-conserved 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 creates a new cryptic intronic 5 donor site. Experimental evidence supports these predictions indicating the variant causes aberrant splicing, which results in a truncated protein (Sidwell_2006). The variant allele was found at a frequency of 4.5e-05 in 246242 control chromosomes (gnomAD). c.555+8A>G has been reported in the literature in multiple homozygous individuals affected with Xeroderma Pigmentosum (e.g. Sidwell_2006, Sethi_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function, demonstrated the variant considerably decreases but does not abolish production of normal XPA protein. This residual protein is able to carry out some low levels of nucleotide excision repair (Sidwell_2006, Sethi_2016). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Ambry Genetics | RCV002553365 | SCV003713848 | pathogenic | Inborn genetic diseases | 2022-07-22 | criteria provided, single submitter | clinical testing | The c.555+8A>G intronic alteration results from a A to G substitution 8 nucleotides after coding exon 4 of the XPA gene. Based on data from gnomAD, the G allele has an overall frequency of <0.01% (11/246242) total alleles studied. The highest observed frequency was 0.04% (11/29322) of South Asian alleles. This alteration has been observed in the homozygous state in multiple individuals with xeroderma pigmentosum (Sidwell, 2006; Fassihi, 2016; Sethi, 2016; Whitworth, 2016). This nucleotide position is not well conserved in available vertebrate species. RNA studies in patient fibroblasts have shown this variant causes aberrant splicing, leading to truncation and decreased production of the XPA protein (Sidwell, 2006; Sethi, 2016). In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. |
| Baylor Genetics | RCV003467782 | SCV004206943 | pathogenic | Xeroderma pigmentosum group A | 2024-02-08 | criteria provided, single submitter | clinical testing |