ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.423A>C (p.Gln141His)

gnomAD frequency: 0.00003  dbSNP: rs143949881
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Total submissions: 3
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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 RCV000802709 SCV005375431 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2024-06-13 reviewed by expert panel curation The c.423A>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Glutamine by Histidine at amino acid 141 (p.Gln141His). The filtering allele frequency (the upper threshold of the 95% CI of 52/1180004 alleles) of the c.423A>C variant in DCLRE1C is 0.00003422 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies. 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): No criteria were applied.
Labcorp Genetics (formerly Invitae), Labcorp RCV000802709 SCV000942551 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2022-08-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 141 of the DCLRE1C protein (p.Gln141His). This variant is present in population databases (rs143949881, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 648065). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc. RCV001272778 SCV001455088 uncertain significance Histiocytic medullary reticulosis 2020-09-16 no assertion criteria provided clinical testing

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