Submissions for variant NM_001033855.3(DCLRE1C):c.47T>C (p.Ile16Thr)

gnomAD frequency: 0.00001  dbSNP: rs1317003987

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001381226	SCV004102784	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-11-14	reviewed by expert panel	curation	The c.47T>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Isoleucine by Tryptophan at amino acid 16 (p.Ile16Thr). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Activity levels in % of WT activity = Recombination: Mean (SD): 79.67 (0.27) and DNA repair (36h after IR): Mean (SD): 80.11 (18.11). The results are bigger than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is NOT Met (PMID: 25917813). At least one patient with this variant displayed Diagnostic criteria for SCID: 0.5pts + T-B-NK+ lymphocyte subset profile: 0.5 pts + Increased cellular radiosensitivity: 0.5pts = Total 1.5 pts, PP4 met, which is highly specific for SCID (PP4 Met) PMIDs: 15770702 and 25917813. Not reported in the literature, but this variant was identified in one patient at Invitae with a clinical diagnosis of SCID (0.5 pts) + a 207 genes immunodeficiency panel ordered, which included all known SCID genes (0.5 points) + severe T and B cell lymphopenia with normal NK cells (CD3: 13, CD19: 0, CD56: 753), consistent with T-B-NK+ SCID (0.5 pts) = totalizing 1.5 pts, PP4 met. Patient 5 is a compound heterozygous with S119X (Pathogenic according to the SCID VCEP specifications, 1 pt, PM3 Met. PMID: 15770702). Not reported in the literature, but this variant was identified in one patient at Invitae with a clinical diagnosis of SCID. In this patient, the variant co-occurred - in trans - confirmed by parental testing - with DCLRE1C deletion (Exons 1-3), pathogenic according to the SCID VCEP specifications: 1 pt. Total: 1+1: 2 pts, PM3_Strong. In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: PM3_Strong, PM2_supporting, PP4 (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001381226	SCV001579530	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 16 of the DCLRE1C protein (p.Ile16Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 15770702; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1069380). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 15770702, 25917813). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323874	SCV004028835	uncertain significance	not specified	2023-07-11	criteria provided, single submitter	clinical testing	Variant summary: DCLRE1C c.47T>C (p.Ile16Thr) results in a non-conservative amino acid change located in the metallo-beta-lactamase domain (Musio_2005, Felgentreff_2015) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251244 control chromosomes (gnomAD v2.1, Exomes dataset). c.47T>C has been reported in the literature in at least two compound heterozygous individuals affected with Severe Combined Immunodeficiency (e.g., Musio_2005, Felgentreff_2015, Cowan_2022). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in an approximately 20% reduction in recombination activity and DNA repair activity relative to wild-type in vitro (e.g., Musio_2005, Felgentreff_2015). The following publications have been ascertained in the context of this evaluation (PMID: 25917813, 15770702, 36546626). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014, citing overlapping evidence, and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV003462975	SCV004190891	pathogenic	Histiocytic medullary reticulosis	2023-12-22	criteria provided, single submitter	clinical testing