Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003556078 | SCV004296757 | pathogenic | not provided | 2023-03-18 | criteria provided, single submitter | clinical testing | Disruption of this splice site has been observed in individuals with CHIME syndrome (PMID: 22444671; Invitae). This sequence change affects an acceptor splice site in intron 3 of the PIGL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PIGL are known to be pathogenic (PMID: 22444671). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. ClinVar contains an entry for this variant (Variation ID: 30547). 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. |
| Gene |
RCV003556078 | SCV005325207 | pathogenic | not provided | 2023-12-26 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22444671) |
| Victorian Clinical Genetics Services, |
RCV000023504 | SCV005400584 | pathogenic | CHIME syndrome | 2024-10-08 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with CHIME syndrome (MIM#280000). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes,0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported to be compound heterozygous with a missense variant, p.(Leu167Pro), in a single individual affected with CHIME syndrome (PMID: 22444671; PMID: 11438011). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1010 - Functional evidence for this variant is inconclusive. A fibroblast cell line from an individual with compound heterozygous variants NM_004278.3:c.427-1G>A and NM_004278.3:c.500T>C showed deficiency in cell surface GPI anchor markers, CD59 and aerolysin (PMID: 22444671). (I) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_004278.3:c.500T>C) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000023504 | SCV000044795 | pathogenic | CHIME syndrome | 2012-04-06 | no assertion criteria provided | literature only |