Submissions for variant NM_001033855.3(DCLRE1C):c.346T>C (p.Cys116Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV002302853	SCV004102782	likely pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-11-14	reviewed by expert panel	curation	The NM_001033855.3:c.436T>C variant in DCLRE1C is a missense variant predicted to cause the substitution of cysteine by arginine at amino acid 116 (p.Cys116Arg). This variant is absent from gnomAD and therefore has a population max filtering allele frequency that is below the threshold for PM2_Supporting set by the ClinGen SCID VCEP for DCLRE1C (<0.00003266). This variant has been reported in an individual with SCID (PMID: 36546626). ART012: As per inclusion criteria in supplement files in PMID: 36546626, diagnostic criteria for SCID/leaky SCID is met (0.5 points), and phenotype was corrected by lentiviral gene therapy (CNV test performed, unpublish data) (7 points). Additional information from Dr. Cowan (unpublished): radiation sensitivity testing in the patient's fibroblasts and demonstrated that the Artemis vector (AProArt) corrected the radiation sensitivity both in terms of proliferation and gH2AX production - therefore 2 additional points added as per specification "Vector-based complementation corrected increased cellular radiosensitivity and/or decreased VDJ recombination." Therefore the total from this patient, by PMID plus unpublished data, is = 9.5 points = PP4_Strong. In this individual, the variant co-occurred in trans with a second variant c.161+2T>G, which would be classified as Likely Pathogenic by the ClinGen SCID VCEP; therefore, PM3 is met (1p). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal recessive SCID based on the ACMG criteria applied: PM2_Supporting, PP4_Strong, and PM3 as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Cowan and Puck Lab, Allergy Immunology and BMT Division, UCSF Benioff Children's Hospital	RCV002302853	SCV002589114	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2021-03-23	criteria provided, single submitter	clinical testing	1 PS3(functional study: Cowan M, Puck J, Unpublished data); 1 PM3(in trans with pathogenic variant); 1 PM2(rare); 1 PP3(Polyphen 1.0 damaging); 1 PP4(phenotype consistent)