Variant: NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)

CA213680

35998 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

UUID: a85e5f2e-f699-4ccb-b9a9-96bc25475fc4

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_001033855.3:c.457G>A
NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)
NC_000010.11:g.14935470C>T
CM000672.2:g.14935470C>T
NC_000010.10:g.14977469C>T
CM000672.1:g.14977469C>T
NC_000010.9:g.15017475C>T
NG_007276.1:g.23626G>A
ENST00000378278.7:c.457G>A
ENST00000357717.6:c.112G>A
ENST00000378241.5:c.97G>A
ENST00000378246.6:c.112G>A
ENST00000378249.5:c.112G>A
ENST00000378254.5:c.97G>A
ENST00000378255.5:c.97G>A
ENST00000378258.5:c.97G>A
ENST00000378278.6:c.457G>A
ENST00000378289.8:c.457G>A
ENST00000396817.6:c.97G>A
ENST00000418843.5:c.19G>A
ENST00000456122.1:c.112G>A
NM_001033855.2:c.457G>A
NM_001033857.2:c.97G>A
NM_001033858.2:c.97G>A
NM_001289076.1:c.112G>A
NM_001289077.1:c.97G>A
NM_001289078.1:c.112G>A
NM_001289079.1:c.97G>A
NM_022487.3:c.112G>A
NR_110297.1:n.1091G>A
NM_001350965.1:c.457G>A
NM_001350966.1:c.112G>A
NM_001350967.1:c.97G>A
NR_146960.1:n.879G>A
NR_146961.1:n.908G>A
NR_146962.1:n.879G>A
NM_001033857.3:c.97G>A
NM_001033858.3:c.97G>A
NM_001289076.2:c.112G>A
NM_001289077.2:c.97G>A
NM_001289078.2:c.112G>A
NM_001289079.2:c.97G>A
NM_001350965.2:c.457G>A
NM_001350966.2:c.112G>A
NM_001350967.2:c.97G>A
NM_022487.4:c.112G>A
NR_110297.2:n.755G>A
NR_146961.2:n.572G>A

Benign

• Met criteria codes: BS2_Supporting BA1

• Not Met criteria codes: PS3

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.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg). The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting). Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

Met criteria codes

• BS2_Supporting: 19 adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting).
• BA1: The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, there are 19 homozygous individuals present in gnomAD.

Not Met criteria codes

• PS3: An in vitro assay demonstrated that the missense variant does not negatively affect V(D)J recombination (Mean 101.8%, 0.45 SD, compared to WT) nor DNA repair (Mean 110%, 7.03 SD compared to WT).