Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Diagnostic and Treatment Unit for Congenital Metabolic Diseases, |
RCV002283348 | SCV002571713 | pathogenic | Sengers syndrome | 2021-12-15 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003492749 | SCV004240842 | pathogenic | AGK-related disorder | 2023-12-01 | criteria provided, single submitter | clinical testing | Variant summary: AGK c.518+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two computational tools predict a significant impact on normal splicing. A recent report confirmed this prediction, by demonstrating that the variant resulted in aberrant splicing in a patient derived sample (Barbosa-Gouveia_2021). The variant allele was absent in 251244 chromosomes (gnomAD v2.1). The variant has been reported in two homozygous patients affected with Sengers Syndrome (e.g. Jou_2019, Barbosa-Gouveia_2021a, Barbosa-Gouveia_2021b). One of these studies also reported in vitro functional evidence, demonstrating reduced electron flow through the mitochondrial respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V (Barbosa-Gouveia_2021b). The following publications have been ascertained in the context of this evaluation (PMID: 30634555, 34440436, 34948281). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |