ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.103C>G (p.His35Asp)

dbSNP: rs121908159
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV001388406 SCV004242273 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-23 reviewed by expert panel curation The c.103C>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Histidine by Aspartic Acid at amino acid 35 (p.His35Asp). The highest population minor allele frequency in gnomAD v4 is 0.000003100 (8/1111884 alleles) in the European (non-Finnish) population, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, meeting this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. Activity levels in % of WT activity = Recombination: Mean (SD): 0 (0.3) and DNA repair (36h after IR): Mean (SD): 27.29 (16.57). PS3 is Met at a moderate level (PMID: 25917813). This variant has been detected in at least 4 individuals with SCID. Of those individuals, 02 were compound heterozygous for the variants: c.2T>C (p.Met1Thr) VUS according to SCID VCEP, 0.25pts AND p.L187*; Pathogenic according to the SCID VCEP specifications, 1 point. 02 individuals were homozygous for the variants (1 point). The total is 2.25 points, PM3_Strong. (PMIDs: 24481607, 15731174, and 32441320). At least one patient with this variant displayed T-B-NK+ (0.5 pts) + Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met (0.5 pts) + Family history of SCID (0.5 pts) + SCID gene panel or exome/genome sequencing conducted (0.5 pts), totaling 2 points, which is highly specific for SCID (PP4_Moderate, PMID: 24481607). In summary, this variant is classified as a Pathogenic for autosomal recessive SCID based on ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP (specification version 1.0): PM3_Strong, PS3_Moderate, PP1_Supporting, PP4_Moderate, and PM2_Supporting.
Illumina Laboratory Services, Illumina RCV000004938 SCV000915466 likely pathogenic Histiocytic medullary reticulosis 2018-02-16 criteria provided, single submitter clinical testing The DCLRE1C c.103C>G (p.His35Asp) missense variant has been reported in a single study in which it was identified in a compound heterozygous state in two related individuals (Ege at al. 2005). One proband was clinically diagnosed with Omenn syndrome with symptoms including sepsis, failure to thrive, generalized lymphedema, hepatomegaly, splenomegaly, and erythrodermatitis. The brother was clinically diagnosed with thrombocytopenia and autoimmune hemolytic anemia with a possible diagnosis of Evans syndrome (Ege et al. 2005). Control data are unavailable for the p.His35Asp variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database. The p.His35Asp variant causes significantly reduced recombination activity and DNA repair as well as loss of endonuclease activity (Pannicke et al. 2004; Pannicke et al. 2010; Felgentreff et al. 2015). The mean activity level in comparison to the wild type, endogenous control activity for the c.103C>G variant is 0% for mean recombination and 27.29% for mean DNA repair (Felgentreff et al. 2015). Based on the available evidence, the c.103C>G (p.His35Asp) variant is classified as likely pathogenic for Omenn syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001388406 SCV001589382 pathogenic Severe combined immunodeficiency due to DCLRE1C deficiency 2023-07-17 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 35 of the DCLRE1C protein (p.His35Asp). This variant is present in population databases (rs121908159, gnomAD 0.0009%). This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 15731174, 24144642). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 4674). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects DCLRE1C function (PMID: 15731174, 25917813). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000004938 SCV004190886 pathogenic Histiocytic medullary reticulosis 2023-10-12 criteria provided, single submitter clinical testing
OMIM RCV000004938 SCV000025114 pathogenic Histiocytic medullary reticulosis 2005-06-01 no assertion criteria provided literature only

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