Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780297 | SCV000917459 | likely pathogenic | Fabry disease | 2019-08-13 | criteria provided, single submitter | clinical testing | Variant summary: GLA c.1000-10G>A 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: Two predict the variant abolishes a 3' acceptor site. One predict the variant weakens a 3' acceptor site. Two predict the variant strenghtens a cryptic intronic 3' acceptor site. These changes would have a predicted effect of the insertion of TTTTTCAG (intronic sequence) into exon 7 leading to G334Ffs*17 (Alamut). Additionally, via patient mRNA sequencing, the variant was reported to lead to insertion of 8 nucleotides between exon 6 and 7, leading to a frameshift at the protien level (data not published, personal correspondence [August 13, 2019]). The variant was absent in 177406 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1000-10G>A has been reported in the literature in a late-onset male Fabry patient with renal insufficiency and cardiac hypertrophy and GLA activity of 23.5% of WT (Lender_2017, Uceyler_2011). These data do not allow any conclusion about variant significance. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, nor is the variant present in HGMD or the Fabry disease database. Based on the evidence outlined above, the variant was classified as likely pathogenic. |