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]

Link to SEPIO compliant JSON-LD document

Variant: NM_001033855.3(DCLRE1C):c.2T>C (p.Met1Thr)

CA117009

4677 (ClinVar)

Gene: DCLRE1C

Condition: severe combined immunodeficiency due to DCLRE1C deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: b821ac51-0f6e-4d6f-8540-0ea50035319a

HGVS expressions

NM_001033855.3:c.2T>C

NM_001033855.3(DCLRE1C):c.2T>C (p.Met1Thr)

NC_000010.11:g.14954009A>G

CM000672.2:g.14954009A>G

NC_000010.10:g.14996008A>G

CM000672.1:g.14996008A>G

NC_000010.9:g.15036014A>G

NG_007276.1:g.5087T>C

ENST00000378278.7:c.2T>C

ENST00000357717.6:c.-203T>C

ENST00000378241.5:c.-571T>C

ENST00000378246.6:c.-288T>C

ENST00000378249.5:c.-236T>C

ENST00000378254.5:c.-490T>C

ENST00000378255.5:c.-812T>C

ENST00000378258.5:c.-444T>C

ENST00000378278.6:c.2T>C

ENST00000378289.8:c.2T>C

ENST00000396817.6:c.-766T>C

ENST00000418843.5:c.-527T>C

ENST00000456122.1:c.-695T>C

NM_001033855.2:c.2T>C

NM_001033857.2:c.-444T>C

NM_001033858.2:c.-766T>C

NM_001289076.1:c.-203T>C

NM_001289077.1:c.-490T>C

NM_001289078.1:c.-236T>C

NM_001289079.1:c.-812T>C

NM_022487.3:c.-288T>C

NR_110297.1:n.424T>C

NM_001350965.1:c.2T>C

NM_001350966.1:c.-236T>C

NM_001350967.1:c.-444T>C

NR_146960.1:n.424T>C

NR_146961.1:n.424T>C

NR_146962.1:n.424T>C

NM_001033857.3:c.-444T>C

NM_001033858.3:c.-766T>C

NM_001289076.2:c.-203T>C

NM_001289077.2:c.-490T>C

NM_001289078.2:c.-236T>C

NM_001289079.2:c.-812T>C

NM_001350965.2:c.2T>C

NM_001350966.2:c.-236T>C

NM_001350967.2:c.-444T>C

NM_022487.4:c.-288T>C

NR_110297.2:n.88T>C

NR_146961.2:n.88T>C

Uncertain Significance

PM2_Supporting PP4 PP1 PVS1_Supporting

BS2 PS3 PM3

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.2T>C (p.Met1Thr) (NM_001033855.3) is a missense variant predicted to cause the substitution of Methionine by Threonine at amino acid 1 (p.Met1Thr). The next possible initiation codon is at codon 8. This region does not contain known pathogenic/likely pathogenic variants, PVS1_Supporting. The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68040 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). At least one patient was observed in the literature (PMID: 15731174) presenting: * Diagnostic criteria for Omenn syndrome (0.5pt) + * Increased cellular radiosensitivity (0.5pt) = total 1 point, PP4_Supporting. The variant has been reported to segregate with OS in - at least - 02 affected family members (proband + one brother) from one family (PP1_Supporting). The patient also had another affected brother without genomic information (PMID: 15731174). This patient is compound heterozygous with c.103C>G (H35D). Phase is confirmed; Pathogenic according to the SCID VCEP specifications; Not counted here to avoid circularity. Two functional assays were found: PMID: 15731174 shows that the ARTEMIS variant (M1T) resulted in a V(D)J recombination efficiency of 2.1% to 2.7%. This corresponds to a recombination efficiency of between 37% and 48% when compared with the assay with WT-ARTEMIS (Which is higher than our threshold, 25%. In the second reference, the activity levels (in % of WT activity) are Recombination (Mean, SD): 80.41, 4.77 and DNA repair (Mean, SD): 76.04, 6.43. Both exceed the established threshold for PS3 (<25% of wild-type activity). With this, PS3 is not applied at any level of evidence. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: (specification version 1.0): PVS1_Supporting, PM2_Supporting, PP1_Supporting, and PP4_Supporting.

PM2_Supporting

The highest population minor allele frequency in gnomAD v4 is 0.00001470 (1/68040 alleles) in European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting).

PP4

PMID: 15731174, patient present: Diagnostic criteria for Omenn syndrome (0.5pt) + Increased cellular radiosensitivity (0.5pt) = total 1 point, PP4_Supporting.

PP1

The variant has been reported to segregate with OS in - at least - 02 affected family members (proband + one brother) from one family (PP1_Supporting). The patient also had another affected brother without genomic information; PMID: 15731174.

PVS1_Supporting

The next possible initiation codon is at codon 8. This region does not contain known pathogenic/likely pathogenic variants. PVS1_Supporting.

BS2

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

PS3

Two functional assays were found: PMID: 15731174 shows that the ARTEMIS variant (M1T) resulted in a V(D)J recombination efficiency of 2.1% to 2.7%. This corresponds to a recombination efficiency of between 37% and 48% when compared with the assay with WT-ARTEMIS (Which is higher than our threshold, 25%. In the second reference, the activity levels (in % of WT activity) are Recombination (Mean, SD): 80.41, 4.77 and DNA repair (Mean, SD): 76.04, 6.43. Both exceed the established threshold for PS3 (<25% of wild-type activity). With this, PS3 is not applied at any level of evidence.

PM3

PMID: 25917813: The patient is compound heterozygous with c.103C>G (H35D). Phase is confirmed; P according to the SCID VCEP. Not counted here to avoid circularity.

Approved on: 2024-01-23

Published on: 2024-01-23

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