Variant: NM_001033855.3(DCLRE1C):c.109+1G>T

CA5417032

969751 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: fb1197f0-344f-42fe-a26d-aeccfa44b7d2

Approved on: 2024-01-23

Published on: 2024-01-23

HGVS expressions

NM_001033855.3:c.109+1G>T
NM_001033855.3(DCLRE1C):c.109+1G>T
NC_000010.11:g.14953901C>A
CM000672.2:g.14953901C>A
NC_000010.10:g.14995900C>A
CM000672.1:g.14995900C>A
NC_000010.9:g.15035906C>A
NG_007276.1:g.5195G>T
ENST00000378278.7:c.109+1G>T
ENST00000357717.6:c.-96+1G>T
ENST00000378241.5:c.-464+1G>T
ENST00000378246.6:c.-181+1G>T
ENST00000378249.5:c.-129+1G>T
ENST00000378254.5:c.-383+1G>T
ENST00000378255.5:c.-705+1G>T
ENST00000378258.5:c.-337+1G>T
ENST00000378278.6:c.109+1G>T
ENST00000378289.8:c.109+1G>T
ENST00000396817.6:c.-659+1G>T
ENST00000418843.5:c.-420+1G>T
ENST00000456122.1:c.-588+1G>T
NM_001033855.2:c.109+1G>T
NM_001033857.2:c.-337+1G>T
NM_001033858.2:c.-659+1G>T
NM_001289076.1:c.-96+1G>T
NM_001289077.1:c.-383+1G>T
NM_001289078.1:c.-129+1G>T
NM_001289079.1:c.-705+1G>T
NM_022487.3:c.-181+1G>T
NR_110297.1:n.531+1G>T
NM_001350965.1:c.109+1G>T
NM_001350966.1:c.-129+1G>T
NM_001350967.1:c.-337+1G>T
NR_146960.1:n.531+1G>T
NR_146961.1:n.531+1G>T
NR_146962.1:n.531+1G>T
NM_001033857.3:c.-337+1G>T
NM_001033858.3:c.-659+1G>T
NM_001289076.2:c.-96+1G>T
NM_001289077.2:c.-383+1G>T
NM_001289078.2:c.-129+1G>T
NM_001289079.2:c.-705+1G>T
NM_001350965.2:c.109+1G>T
NM_001350966.2:c.-129+1G>T
NM_001350967.2:c.-337+1G>T
NM_022487.4:c.-181+1G>T
NR_110297.2:n.195+1G>T
NR_146961.2:n.195+1G>T

Pathogenic

• Met criteria codes: PM2_Supporting PM3 PVS1

• Not Met criteria codes: PP4

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.109+1G>T (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+1) of intron 1. It is predicted to cause skipping of biologically relevant exon 1/14, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This prediction is confirmed by RT-PCR analysis (PMID: 25981738). The filtering allele frequency (the upper threshold of the 95% CI of 5/128202 of the c.109+1G>T variant in DCLRE1C is 0.00001128 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). This variant has been detected in at least one individual in the literature. Patient 6, PMID: 25981738, is compound heterozygous with 82kb hemizygous deletion involving exons 1–4 of DCLRE1C, at least LP, according to SCID VCEP. 1 point, PM3 is met. 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: PM2_Supporting, PVS1, and PM3 (VCEP specifications version 1).

Met criteria codes

• PM2_Supporting: The filtering allele frequency (the upper threshold of the 95% CI of 5/128202 of the c.109+1G>T variant in DCLRE1C is 0.00001128 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).
• PM3: Patient 6, PMID: 25981738 is compoud het. with 82kb hemizygous deletion involving exons 1–4 of DCLRE1C, alt least LP according to SCID VCEP. 1 point, PM3 is met.
• PVS1: The c.109+1G>T (NM_001033855.3) variant in DCLRE1C occurs within the canonical splice donor site (+1) of intron 1. It is predicted to cause skipping of biologically relevant exon 1/14, resulting in a frameshift leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This prediction is confirmed by RT-PCR analysis (PMID: 25981738).

Not Met criteria codes

• PP4: There is insufficient information available to apply PP4 to any level of evidence strength.