Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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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

Link to MONDO

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

PP4_Moderate PVS1_Moderate PM2_Supporting PP1

PM3 PS3

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

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).

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).

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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PP1

There are 2 patients who are siblings (Family A, P4, and P5) (PMID: 26476407, PP1_supporting).

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.

PS3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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