Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

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
ENST00000378241.6:c.*1857dup
ENST00000456122.2:c.*1343-9506dup
ENST00000489161.2:c.*1392dup
ENST00000492201.6:c.*663dup
ENST00000697047.1:c.1669dup
ENST00000697070.1:c.1669dup
ENST00000697071.1:c.*1589dup
ENST00000697072.1:c.*681dup
ENST00000697073.1:c.*1447dup
ENST00000697074.1:c.*1447dup
ENST00000697075.1:c.1669dup
ENST00000697076.1:c.*681dup
ENST00000697077.1:c.*1380dup
ENST00000697078.1:c.*1376dup
ENST00000697079.1:n.1373dup
ENST00000697080.1:c.*1533dup
ENST00000697081.1:c.*1427dup
ENST00000697082.1:c.*1698dup
ENST00000697083.1:c.*1474dup
ENST00000697084.1:c.1726dup
ENST00000697085.1:c.*1436dup
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
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PP1 PVS1_Moderate PP4_Moderate
Not Met criteria codes 2
PM3 PS3

Evidence Links 0

Expert Panel

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).
Met criteria codes
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).
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).
Not Met criteria codes
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
Curation History
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