ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.457G>A (p.Gly153Arg)

gnomAD frequency: 0.00964  dbSNP: rs41297018
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Total submissions: 14
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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 RCV000560374 SCV004102786 benign Severe combined immunodeficiency due to DCLRE1C deficiency 2023-11-14 reviewed by expert panel curation The c.457G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Arginine at amino acid 153 (p.Gly153Arg). The filtering allele frequency (the lower threshold of the 95% CI of 2195/129158) of the c.457G>A variant in DCLRE1C is 0.01641 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen SCID VCEP threshold >0.00346 for BA1, and therefore meets this criterion (BA1). Also, nineteen (19) adult homozygous individuals with this variant are present in gnomADv2.1.1 (European non-Finnish n=15, European (Finnish) n=1, Latino/Admixed American n=1, South Asian n=2)(BS2_Supporting). Additionally, a functional study showed non-dysfunction of V(D)J recombination and DNA repair (around 100% compared to wild type), and we do not find this variant described in patients with SCID due to DCLRE1C deficiency after a comprehensive literature search. In summary, this variant meets the criteria to be classified as Benign for autosomal recessive SCID based on the ACMG/AMP criteria applied, BA1 and BS2_Supporting, as specified by the ClinGen SCID VCEP (VCEP specifications version 1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000455778 SCV000052308 benign not specified 2018-03-09 criteria provided, single submitter clinical testing Variant summary: DCLRE1C c.457G>A (p.Gly153Arg) results in a non-conservative amino acid change located in the Metallo-beta-lactamase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 120654 control chromosomes in the ExAC database, including 12 homozygotes. The observed variant frequency is approximately 2.72 fold of the estimated maximal expected allele frequency for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency Syndrome phenotype (0.0041), strongly suggesting that the variant is benign. c.457G>A has been reported in the literature in individuals affected with Severe Combined Immunodeficiency Syndrome. These report(s) do not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224125 SCV000280758 likely benign not provided 2015-09-02 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000455778 SCV000538776 likely benign not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant associated with SCID, but high frequency and a functional study suggests no impact on activity.
Labcorp Genetics (formerly Invitae), Labcorp RCV000560374 SCV000645228 benign Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-31 criteria provided, single submitter clinical testing
GeneDx RCV000455778 SCV000720401 benign not specified 2017-01-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Mendelics RCV000560374 SCV001138004 benign Severe combined immunodeficiency due to DCLRE1C deficiency 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000224125 SCV001156850 benign not provided 2023-08-28 criteria provided, single submitter clinical testing
New York Genome Center RCV000560374 SCV001622933 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2020-07-09 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000224125 SCV002544412 benign not provided 2024-02-01 criteria provided, single submitter clinical testing DCLRE1C: BS1, BS2
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224106 SCV003919872 likely benign Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis 2022-10-13 criteria provided, single submitter clinical testing This variant has been reported in the literature in at least 3 individuals with clinical phenotypes of Severe Combined Immunodeficiency (SCID) or Inflammatory Bowel Disease (IBD) (Lagresle-Peyrou 2008 PMID:18223550, Ashton 2020 PMID:32463623). This variant is present in the Genome Aggregation Database (Highest reported MAF 1.7% (2195/129158) including 15 homozygotes (https://gnomad.broadinstitute.org/variant/10-14977469-C-T?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:35998). In vitro functional studies predict that this variant will not impact the protein (Felgentreff 2015 PMID:25333069). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign.
Natera, Inc. RCV001272391 SCV001454375 benign Histiocytic medullary reticulosis 2019-12-09 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000455778 SCV001742669 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000224125 SCV001931715 likely benign not provided no assertion criteria provided clinical testing

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