Variant: NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)

CA5416778

1322192 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: a70f8802-2cb7-4ec3-a96e-180feda5744f

Approved on: 2024-03-08

Published on: 2024-03-08

HGVS expressions

NM_001033855.3:c.571C>T
NM_001033855.3(DCLRE1C):c.571C>T (p.Arg191Ter)
NC_000010.11:g.14934487G>A
CM000672.2:g.14934487G>A
NC_000010.10:g.14976486G>A
CM000672.1:g.14976486G>A
NC_000010.9:g.15016492G>A
NG_007276.1:g.24609C>T
ENST00000378241.6:c.*618C>T
ENST00000456122.2:c.*757C>T
ENST00000489161.2:c.*349C>T
ENST00000492201.6:c.571C>T
ENST00000697047.1:c.571C>T
ENST00000697070.1:c.571C>T
ENST00000697071.1:c.*491C>T
ENST00000697072.1:c.571C>T
ENST00000697073.1:c.*349C>T
ENST00000697074.1:c.*349C>T
ENST00000697075.1:c.571C>T
ENST00000697076.1:c.571C>T
ENST00000697077.1:c.*282C>T
ENST00000697078.1:c.*278C>T
ENST00000697079.1:n.275C>T
ENST00000697080.1:c.*435C>T
ENST00000697081.1:c.*188C>T
ENST00000697082.1:c.*757C>T
ENST00000697083.1:c.*431C>T
ENST00000697084.1:c.571C>T
ENST00000697085.1:c.*338C>T
ENST00000697086.1:n.3008C>T
ENST00000697087.1:c.*491C>T
ENST00000697088.1:c.*188C>T
ENST00000697089.1:c.*491C>T
ENST00000697090.1:n.579C>T
ENST00000378278.7:c.571C>T
ENST00000357717.6:c.226C>T
ENST00000378241.5:c.211C>T
ENST00000378246.6:c.226C>T
ENST00000378249.5:c.226C>T
ENST00000378254.5:c.211C>T
ENST00000378255.5:c.211C>T
ENST00000378258.5:c.211C>T
ENST00000378278.6:c.571C>T
ENST00000378289.8:c.571C>T
ENST00000396817.6:c.211C>T
ENST00000418843.5:c.133C>T
NM_001033855.2:c.571C>T
NM_001033857.2:c.211C>T
NM_001033858.2:c.211C>T
NM_001289076.1:c.226C>T
NM_001289077.1:c.211C>T
NM_001289078.1:c.226C>T
NM_001289079.1:c.211C>T
NM_022487.3:c.226C>T
NR_110297.1:n.1205C>T
NM_001350965.1:c.571C>T
NM_001350966.1:c.226C>T
NM_001350967.1:c.211C>T
NR_146960.1:n.993C>T
NR_146961.1:n.1022C>T
NR_146962.1:n.993C>T
NM_001033857.3:c.211C>T
NM_001033858.3:c.211C>T
NM_001289076.2:c.226C>T
NM_001289077.2:c.211C>T
NM_001289078.2:c.226C>T
NM_001289079.2:c.211C>T
NM_001350965.2:c.571C>T
NM_001350966.2:c.226C>T
NM_001350967.2:c.211C>T
NM_022487.4:c.226C>T
NR_110297.2:n.869C>T
NR_146961.2:n.686C>T

Pathogenic

• Met criteria codes: PS3_Moderate PVS1 PM2_Supporting

• Not Met criteria codes: BS2

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 c.571C>T (p.Arg191Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). The filtering allele frequency (the upper threshold of the 95% CI of 2/86258 alleles) of the c.571C>T variant in DCLRE1C is 0.000003850 for South Asian 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). No homozygotes have been observed in gnomAD. Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.87) and DNA repair (36h after IR): Mean (SD): 0 (12.11). 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). 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. Criteria applied: PVS1, PM2_Supporting, and PS3_Moderate (VCEP specifications version 1).

Met criteria codes

• PS3_Moderate: Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.87) and DNA repair (36h after IR): Mean (SD): 0 (12.11). 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 c.571C>T (p.Arg191Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 8/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met).
• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 2/86258 alleles) of the c.571C>T variant in DCLRE1C is 0.000003850 for South Asian 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). No homozygotes have been observed in gnomAD.

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline