ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.82G>C (p.Ala28Pro)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV003062253 SCV004242279 likely pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-23 reviewed by expert panel curation The c.82G>C(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Alanine by Proline at amino acid 28 (p.Ala28Pro). This variant is absent from gnomAD v4 (PM2_Supporting). At least one patient with this variant displayed Decreased V(D)J recombination 0.5pts + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5 pts. + T−B−NK+ 0.5pts + Increased cellular radiosensitivity 0.5pts. The total is 2 points, which is highly specific for SCID (PP4_Moderate, PMIDs 19953608 and 25917813). The patient is homozygous, 0.5pts. PM3_Supporting. Activity levels in % of WT activity = Recombination: Mean (SD): 3.00 (0.15) and DNA repair (36h after IR): Mean (SD): 5.13 (11.95). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level(PMID: 25917813). In summary, this variant is classified as a Likely Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM2_Supporting, PP4_Moderate, PM3_Supporting, and PS3_Moderate.
Invitae RCV003062253 SCV003441412 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2022-07-15 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 25917813). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 19953608). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 28 of the DCLRE1C protein (p.Ala28Pro).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.