Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001033855.3(DCLRE1C):c.194C>T (p.Thr65Ile)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA10586373

254217 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 3fe92f1e-0ee4-4f50-aaa3-923da18fc227

Approved on: 2024-01-17

Published on: 2024-01-17

HGVS expressions

NM_001033855.3:c.194C>T

NM_001033855.3(DCLRE1C):c.194C>T (p.Thr65Ile)

NC_000010.11:g.14945157G>A

CM000672.2:g.14945157G>A

NC_000010.10:g.14987156G>A

CM000672.1:g.14987156G>A

NC_000010.9:g.15027162G>A

NG_007276.1:g.13939C>T

ENST00000378278.7:c.194C>T

ENST00000357717.6:c.-44+3879C>T

ENST00000378241.5:c.-294C>T

ENST00000378246.6:c.-96C>T

ENST00000378249.5:c.-96C>T

ENST00000378254.5:c.-167C>T

ENST00000378255.5:c.-489C>T

ENST00000378258.5:c.-167C>T

ENST00000378278.6:c.194C>T

ENST00000378289.8:c.194C>T

ENST00000396817.6:c.-489C>T

ENST00000418843.5:c.-204C>T

ENST00000456122.1:c.-418C>T

NM_001033855.2:c.194C>T

NM_001033857.2:c.-167C>T

NM_001033858.2:c.-489C>T

NM_001289076.1:c.-44+3879C>T

NM_001289077.1:c.-167C>T

NM_001289078.1:c.-96C>T

NM_001289079.1:c.-489C>T

NM_022487.3:c.-96C>T

NR_110297.1:n.701C>T

NM_001350965.1:c.194C>T

NM_001350966.1:c.-96C>T

NM_001350967.1:c.-167C>T

NR_146960.1:n.616C>T

NR_146961.1:n.701C>T

NR_146962.1:n.616C>T

NM_001033857.3:c.-167C>T

NM_001033858.3:c.-489C>T

NM_001289076.2:c.-44+3879C>T

NM_001289077.2:c.-167C>T

NM_001289078.2:c.-96C>T

NM_001289079.2:c.-489C>T

NM_001350965.2:c.194C>T

NM_001350966.2:c.-96C>T

NM_001350967.2:c.-167C>T

NM_022487.4:c.-96C>T

NR_110297.2:n.365C>T

NR_146961.2:n.365C>T

Pathogenic

PP1_Strong PP4_Moderate PM2_Supporting PM3_Strong

PS3

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The c.194C>T(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Threonine by Isoleucine at amino acid 65 p.Thr65Ile. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID: 26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID: 26476407) (PM3_moderate); For 1 individual (PMID: 25917813), the second allele information wasn't available. The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID: 26476407). At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate). In summary, this variant meets the criteria to be classified as pathogenic for autosomal recessive SCID based on the ACMG/AMP criteria applied, PP4_Moderate, PP1_Strong, PM3_Strong, PM2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).

PP1_Strong

The variant has been reported to segregate with SCID in 7 affected family members from 3 families (Family A: Proband + 4; Family D: Proband + 2; Family E: Proband + 1 = 7 segregations, LOD: 4.21); PP1_Strong; PMID: 26476407).

PP4_Moderate

At least one patient with this variant displayed Vector-based complementation corrected increased cellular radiosensitivity and/or decreased V(D)J recombination (P1, 2 and 5, 2 pts, PMID:26476407, PP4_moderate). Also, PMID: 25917813: Diagnostic criteria for Leaky SCID: 0,5 pt + T-B-NK+ lymphocyte subset profile: 0.5 pt. (Total 1 pt. PP4_supporting).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

PM3_Strong

This variant has been detected in at least 13 individuals with SCID/Lealy SCID/Omen. Of those individuals, 2 were compound heterozygous for the variant p.T577Nfs*21 (Likely Likely Pathogenic according to the SCID VCEP specifications - confirmed in trans by family testing (PMID: 26476407, 2 pts). 10 individuals were homozygous for the variant (1 point limit was reached - PMID: 26476407) (PM3_moderate); For 1 individual (PMID: 25917813) the second allele information wasn't available.

PS3

PMID: 25917813 = An in vitro assay demonstrated that the missense variant does not negatively affect V(D)J recombination, Mean: 83.75, SD: 1.32 nor DNA repair, Mean 89.45, SD 14.05 (both compared to WT).

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.