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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
Link to MONDO
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 2
BS2_Supporting BA1
Not Met criteria codes 1
PS3

Evidence Links 1

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 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).
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). PubMed:25917813
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