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

gnomAD frequency: 0.00964  dbSNP: rs41297018

Total submissions: 14

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.
Invitae	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