Submissions for variant NM_001033855.3(DCLRE1C):c.985T>A (p.Leu329Met)

gnomAD frequency: 0.00071  dbSNP: rs41299658

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000295727	SCV000361551	uncertain significance	Histiocytic medullary reticulosis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV000560174	SCV000645231	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 329 of the DCLRE1C protein (p.Leu329Met). This variant is present in population databases (rs41299658, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with common variable immunodeficiency (CVID) (PMID: 26122175). ClinVar contains an entry for this variant (Variation ID: 299316). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DCLRE1C protein function. 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.
GeneDx	RCV001555221	SCV001776599	uncertain significance	not provided	2021-06-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in a patient with common variable immunodeficiency in published literature (van Schouwenburg et al., 2015); however a second DCLRE1C variant was not identified; This variant is associated with the following publications: (PMID: 26122175)
Fulgent Genetics, Fulgent Genetics	RCV002494927	SCV002781888	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis	2022-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155155	SCV003844862	uncertain significance	not specified	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: DCLRE1C c.985T>A (p.Leu329Met) results in a conservative amino acid change located in the DNA repair metallo-beta-lactamase domain (IPR011084) 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 0.00067 in 251182 control chromosomes (gnomAD), predominantly at a frequency of 0.0014 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency phenotype (0.00071), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.985T>A has been reported in the literature in individuals affected with sporadic common variable immunodeficiency (van Schouwenburg_2015). This report does not provide unequivocal conclusions about association of the variant with Severe Combined Immunodeficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Natera, Inc.	RCV001833429	SCV002079820	uncertain significance	Athabaskan severe combined immunodeficiency	2020-08-04	no assertion criteria provided	clinical testing