Submissions for variant NM_001033855.3(DCLRE1C):c.241C>T (p.Arg81Ter)

gnomAD frequency: 0.00003  dbSNP: rs121908156

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000004929	SCV004242275	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-01-23	reviewed by expert panel	curation	The NM_001033855.3:c.241C>T (p.Arg81Ter) variant in DCLRE1C is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon, 3/14, which is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). The filtering allele frequency (the upper threshold of the 95% CI of 38/1177816 alleles) of the c.241C>T variant in DCLRE1C is 0.00002205 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). Activity levels in % of WT activity = Recombination: Mean (SD): 19.48 (1.56) and DNA repair (36h after IR): Mean (SD): 16.05 (4.77). Both values are lower than our established threshold for abnormal results (defined as <25% of wild-type activity). Thus, PS3 is Met at a moderate level. (PMID: 25917813). At least one patient with this variant displayed Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome 0.5pts + T-B-NK+ lymphocyte subset profile 0.5pts; the total is 1 point, which is highly specific for SCID (PP4_Supporting, PMID: 11336668). The proband (P2) is homozygous (Table 1) for this variant (0.5pt; PM3_Supporting). 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, PS3_Moderate, and PP4_Supporting (VCEP specifications version 1).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224235	SCV000281229	pathogenic	not provided	2014-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000224235	SCV000329331	pathogenic	not provided	2023-02-02	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect, including significantly reduced protein activity (Felgentreff et al., 2015); This variant is associated with the following publications: (PMID: 30947698, 25525159, 31589614, 25917813, 11336668, 30625039, 35503492)
Fulgent Genetics, Fulgent Genetics	RCV000762806	SCV000893157	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000004929	SCV000941702	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg81*) in the DCLRE1C gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DCLRE1C are known to be pathogenic (PMID: 21664875, 26123418). This variant is present in population databases (rs121908156, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with severe combined immune deficiency (PMID: 11336668, 25917813). This variant is also known as R74X. ClinVar contains an entry for this variant (Variation ID: 4665). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001272780	SCV004190893	pathogenic	Histiocytic medullary reticulosis	2023-09-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003486542	SCV004241908	pathogenic	Severe combined immunodeficiency disease	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: DCLRE1C c.241C>T (p.Arg81X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.2e-05 in 250582 control chromosomes (gnomAD). c.241C>T has been reported in the literature in individuals affected with Severe Combined Immunodeficiency (example: Moshous_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence that this variant impairs normal protein activity (Moshous_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11336668, 12727634). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000004929	SCV000025105	pathogenic	Severe combined immunodeficiency due to DCLRE1C deficiency	2001-04-20	no assertion criteria provided	literature only
Natera, Inc.	RCV001272780	SCV001455090	pathogenic	Histiocytic medullary reticulosis	2020-09-16	no assertion criteria provided	clinical testing