ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.265A>G (p.Thr89Ala)

gnomAD frequency: 0.00004  dbSNP: rs756366535
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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 RCV001243925 SCV004810409 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2024-02-15 reviewed by expert panel curation The c.265A>G (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Threonine by Alanine at amino acid 89 (p.Thr89Ala). The filtering allele frequency (the upper threshold of the 95% CI of 9/89618) of the c.265A>G variant in DCLRE1C is 0.00005480 for South Asian chromosomes by gnomAD v4, which is higher than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore do not meet this criterion. This variant has been observed in a 14-year-old boy with autoimmune hemolytic anemia. He was severely lymphopenic and had evidence of reduced T and B cell numbers and function, including reduced T cell receptor diversity. Leaky SCID could not be confirmed with the limited evidence reported (PMID: 23701501). In summary, due to insufficient evidence, 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 RCV001243925 SCV001417115 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2021-08-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 89 of the DCLRE1C protein (p.Thr89Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This missense change has been observed in individual(s) with autoimmune hemolytic anemia (PMID: 23701501). 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: "Deleterious"; PolyPhen-2: "Benign"; 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.
CeGaT Center for Human Genetics Tuebingen RCV001726465 SCV001961200 uncertain significance not provided 2021-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002491815 SCV002783487 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis 2022-04-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV001835190 SCV002081792 uncertain significance Athabaskan severe combined immunodeficiency 2021-03-04 no assertion criteria provided clinical testing

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