Submissions for variant NM_001033855.3(DCLRE1C):c.1147C>T (p.Arg383Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV002287294	SCV005375425	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-06-13	reviewed by expert panel	curation	The c.1147C>T (p.Arg383Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant that is predicted to escape nonsense-mediated decay; however, removes >10% of the protein with known P/LP variants downstream (PVS1_Strong). The filtering allele frequency (the upper threshold of the 95% CI of 2/39692 alleles) of the c.1147C>T variant in DCLRE1C is 0.000008350 for East Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. This variant has been detected in at least three probands: two are homozygous for this variant PMIDs: 25917813 and 35482138, 1 pt. The third proband is compound heterozygous with c.109 + 2T>C (Paternal - At least Likely Pathogenic, PVS1, and PM2_Supporting) and c.1147C>T;p.R383X (Maternal). 1 pt (PMID: 37901335). Total is 2 pts, PM3_Strong. At least one patient in the literature presents: Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + TmatB−NK+ (0.5 pts), increased cellular radiosensitivity (0.5 pts), and decreased V(D)J recombination (0.5 pts), totaling 2 points, PP4_Moderate (PMIDs: 25917813 and 19953608). 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: PVS1_Strong, PM2_Supporting, PM3_Strong, and PP4_Moderate (VCEP specifications version 1).
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV002287294	SCV002577564	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-02-24	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2, PP3, PP5
Labcorp Genetics (formerly Invitae), Labcorp	RCV002287294	SCV003441609	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg383*) in the DCLRE1C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 310 amino acid(s) of the DCLRE1C protein. This variant is present in population databases (rs752241422, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with SCID (PMID: 19953608). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1708141). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects DCLRE1C function (PMID: 19953608, 25917813). This variant disrupts a region of the DCLRE1C protein in which other variant(s) (p.Thr557Asnfs*21) have been determined to be pathogenic (PMID: 26476407). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.