Submissions for variant NM_024782.3(NHEJ1):c.170G>A (p.Arg57Gln)

gnomAD frequency: 0.00034  dbSNP: rs61753339

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224351	SCV000280753	uncertain significance	not provided	2015-06-04	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690631	SCV000818328	uncertain significance	Cernunnos-XLF deficiency	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 57 of the NHEJ1 protein (p.Arg57Gln). This variant is present in population databases (rs61753339, gnomAD 0.06%). 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: 235289). 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: "Probably 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224351	SCV002542009	uncertain significance	not provided	2021-10-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282062	SCV002570950	uncertain significance	not specified	2022-07-05	criteria provided, single submitter	clinical testing	Variant summary: NHEJ1 c.170G>A (p.Arg57Gln) results in a conservative amino acid change located in the XLF, N-terminal domain (IPR015381) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251482 control chromosomes (gnomAD), predominantly at a frequency of 0.0006 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 NHEJ1 causing Severe Combined Immunodeficiency (0.00035), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.170G>A has been reported in the literature in settings of WGS/WES in at least one heterozygous individual affected with common variable immunodeficiency disorder (CVID) and in a heterozygous individual with very early onset inflammatory bowel disease (e.g. van Schouwenburg_2015, Kelsen_2015). These reports do 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. Two assessments for this variant have been submitted to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GenomeConnect - Invitae Patient Insights Network	RCV000690631	SCV001749539	not provided	Cernunnos-XLF deficiency		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.