Variant: NM_001033855.3(DCLRE1C):c.241C>T (p.Arg81Ter)

CA117001

4665 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: e3e1b71b-a5f7-46e8-ac26-4ef03d6cc5c5

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_001033855.3:c.241C>T
NM_001033855.3(DCLRE1C):c.241C>T (p.Arg81Ter)
NC_000010.11:g.14945110G>A
CM000672.2:g.14945110G>A
NC_000010.10:g.14987109G>A
CM000672.1:g.14987109G>A
NC_000010.9:g.15027115G>A
NG_007276.1:g.13986C>T
ENST00000378278.7:c.241C>T
ENST00000357717.6:c.-44+3926C>T
ENST00000378241.5:c.-247C>T
ENST00000378246.6:c.-49C>T
ENST00000378249.5:c.-49C>T
ENST00000378254.5:c.-120C>T
ENST00000378255.5:c.-442C>T
ENST00000378258.5:c.-120C>T
ENST00000378278.6:c.241C>T
ENST00000378289.8:c.241C>T
ENST00000396817.6:c.-442C>T
ENST00000418843.5:c.-157C>T
ENST00000456122.1:c.-371C>T
NM_001033855.2:c.241C>T
NM_001033857.2:c.-120C>T
NM_001033858.2:c.-442C>T
NM_001289076.1:c.-44+3926C>T
NM_001289077.1:c.-120C>T
NM_001289078.1:c.-49C>T
NM_001289079.1:c.-442C>T
NM_022487.3:c.-49C>T
NR_110297.1:n.748C>T
NM_001350965.1:c.241C>T
NM_001350966.1:c.-49C>T
NM_001350967.1:c.-120C>T
NR_146960.1:n.663C>T
NR_146961.1:n.748C>T
NR_146962.1:n.663C>T
NM_001033857.3:c.-120C>T
NM_001033858.3:c.-442C>T
NM_001289076.2:c.-44+3926C>T
NM_001289077.2:c.-120C>T
NM_001289078.2:c.-49C>T
NM_001289079.2:c.-442C>T
NM_001350965.2:c.241C>T
NM_001350966.2:c.-49C>T
NM_001350967.2:c.-120C>T
NM_022487.4:c.-49C>T
NR_110297.2:n.412C>T
NR_146961.2:n.412C>T

Pathogenic

• Met criteria codes: PP4 PM3_Supporting PS3_Moderate PVS1 PM2_Supporting

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:c.241C>T (p.Arg81Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 38/1177816 alleles) of the c.241C>T variant in DCLRE1C is 0.00002205 for European (non-Finnish) 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). Activity levels in % of WT activity = Recombination: Mean (SD): 19.48 (1.56) and DNA repair (36h after IR): Mean (SD): 16.05 (4.77). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level. (PMID: 25917813). At least one patient with this variant displayed Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, which is highly specific for SCID (PP4_Supporting, PMID: 11336668). The proband (P2) is homozygous (Table 1) for this variant (0.5pt; PM3_Supporting). 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, PM2_Supporting, PM3_Supporting, PS3_Moderate, and PP4_Supporting (VCEP specifications version 1).

Met criteria codes

• PP4: At least one patient with this variant displayed Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, which is highly specific for SCID (PP4_Supporting, PMID: 11336668).
• PM3_Supporting: One proband (P2) is homozygous (Table 1) for this variant (0.5pt; PM3_Supporting). PMID: 11336668
• PS3_Moderate: Activity levels in % of WT activity = Recombination: Mean (SD): 19.48 (1.56) and DNA repair (36h after IR): Mean (SD): 16.05 (4.77). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level. (PMID: 25917813).
• PVS1: The NM_001033855.3:c.241C>T (p.Arg81Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1).
• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 38/1177816 alleles) of the c.241C>T variant in DCLRE1C is 0.00002205 for European (non-Finnish) 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).