Variant: NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557fs)

CA10586372

254216 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: 3a961714-b3e6-4725-8cdd-42ab2ce1a714

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_001033855.3:c.1669dup
NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557fs)
NC_000010.11:g.14908818dup
CM000672.2:g.14908818dup
NC_000010.10:g.14950817dup
CM000672.1:g.14950817dup
NC_000010.9:g.14990823dup
NG_007276.1:g.50278dup
ENST00000378278.7:c.1669dup
ENST00000357717.6:c.1324dup
ENST00000378242.1:c.628dup
ENST00000378246.6:c.1324dup
ENST00000378249.5:c.1324dup
ENST00000378254.5:c.1309dup
ENST00000378255.5:c.1309dup
ENST00000378258.5:c.1309dup
ENST00000378278.6:c.1669dup
ENST00000378289.8:c.1157-9506dup
ENST00000396817.6:c.1309dup
ENST00000492201.5:n.884dup
NM_001033855.2:c.1669dup
NM_001033857.2:c.1309dup
NM_001033858.2:c.1309dup
NM_001289076.1:c.1324dup
NM_001289077.1:c.1309dup
NM_001289078.1:c.1324dup
NM_001289079.1:c.1309dup
NM_022487.3:c.1324dup
NR_110297.1:n.2444dup
NM_001350965.1:c.1669dup
NM_001350966.1:c.1324dup
NM_001350967.1:c.1309dup
NR_146960.1:n.2036dup
NR_146961.1:n.2185dup
NR_146962.1:n.2156dup
NM_001033857.3:c.1309dup
NM_001033858.3:c.1309dup
NM_001289076.2:c.1324dup
NM_001289077.2:c.1309dup
NM_001289078.2:c.1324dup
NM_001289079.2:c.1309dup
NM_001350965.2:c.1669dup
NM_001350966.2:c.1324dup
NM_001350967.2:c.1309dup
NM_022487.4:c.1324dup
NR_110297.2:n.2108dup
NR_146961.2:n.1849dup

Likely Pathogenic

• Met criteria codes: PVS1_Moderate PP4_Moderate PP1 PM2_Supporting

• Not Met criteria codes: PS3 PM3

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DCLRE1C Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557AsnfsTer21) variant in DCLRE1C is a frameshift variant that may cause loss of function of the protein; however, it is predicted that the transcript likely escapes nonsense-mediated decay (PMID: 26476407 supports this notion). Additionally, no downstream pathogenic variants have been curated to date (curated following SCID VCEP specifications). Thus, currently, this variant is limited to PVS1 at moderate strength. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). There are 2 patients who are siblings (Family A, P4, and P5) (PMID: 26476407, PP1_supporting). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P5, 2 pts, PMID:26476407, PP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied: PVS1_Moderate, PM2_Supporting, PP1_Supporting, and PP4_Moderate, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

Met criteria codes

• PVS1_Moderate: The NM_001033855.3(DCLRE1C):c.1669dup (p.Thr557AsnfsTer21) variant in DCLRE1C is a frameshift variant that may cause loss of function of the protein. However, it is predicted to escape nonsense-mediated decay and no variants downstream (according to ClinVar (PVS1_Moderate).
• PP4_Moderate: At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P5, 2 pts, PMID:26476407, PP4_moderate).
• PP1: There are 2 patients who are siblings (Family A, P4, and P5) (PMID: 26476407, PP1_supporting).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM3: Patients 4 and 5 were heterozygous compounds for a second variant (T65I), Pathogenic according to the SCID VCEP specifications. The trans phase was confirmed by parental testing. (PMID: 26476407). However, we can't apply points here because according to the SVI recommendation for in trans criteria we can only apply PM3 for one of them to avoid a circular argument.