Submissions for variant NM_001033855.3(DCLRE1C):c.522C>G (p.Tyr174Ter)

dbSNP: rs1340132582

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000814078	SCV004810425	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-03-08	reviewed by expert panel	curation	The c.522C>G (p.Tyr174Ter)(NM_001033855.3) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 7/14 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1 is met). This variant is absent from gnomAD v4 (PM2_Supporting). One patient reported in the literature is homozygous for this variant, 0.5 pts, PM3_Supporting. She is T-B-NK+ (0.5 pts) with diagnosis carried out through SCID gene panel or exome/genome sequencing conducted (0.5 pts), total 1 pt, PP4_Supporting (PMID: 37480474). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PVS1, PM2_Supporting, PM3_Supporting, and PP4_Supporting (VCEP specifications version 1).
Invitae	RCV000814078	SCV000954475	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2018-10-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr174*) in the DCLRE1C gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). This variant has not been reported in the literature in individuals with DCLRE1C-related disease. This variant is not present in population databases (ExAC no frequency).