Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001245169 | SCV004242282 | pathogenic | Severe combined immunodeficiency due to DCLRE1C deficiency | 2024-01-23 | reviewed by expert panel | curation | The c.109+1G>T (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+1) of intron 1. It is predicted to cause skipping of biologically relevant exon 1/14, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This prediction is confirmed by RT-PCR analysis (PMID: 25981738). The filtering allele frequency (the upper threshold of the 95% CI of 5/128202 of the c.109+1G>T variant in DCLRE1C is 0.00001128 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least one individual in the literature. Patient 6, PMID: 25981738, is compound heterozygous with 82kb hemizygous deletion involving exons 1–4 of DCLRE1C, at least LP, according to SCID VCEP. 1 point, PM3 is met. In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting, PVS1, and PM3 (VCEP specifications version 1). |
Labcorp Genetics |
RCV001245169 | SCV001418439 | pathogenic | Severe combined immunodeficiency due to DCLRE1C deficiency | 2023-06-12 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 969751). Disruption of this splice site has been observed in individual(s) with profound lymphopenia and low T-cell function (PMID: 25981738). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs143144732, gnomAD 0.004%). This sequence change affects a donor splice site in intron 1 of the DCLRE1C 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 DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). |
Baylor Genetics | RCV003469469 | SCV004190921 | pathogenic | Histiocytic medullary reticulosis | 2022-07-18 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005036528 | SCV005667740 | likely pathogenic | Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis | 2024-02-25 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001829948 | SCV002078041 | pathogenic | Athabaskan severe combined immunodeficiency | 2020-11-06 | no assertion criteria provided | clinical testing |