Submissions for variant NM_001033855.3(DCLRE1C):c.572G>A (p.Arg191Gln)

gnomAD frequency: 0.00003  dbSNP: rs528699445

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001215552	SCV005375436	likely benign	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-06-13	reviewed by expert panel	curation	The c.572G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Arginine by Glutamine at amino acid 191 (p.Arg191Gln). The filtering allele frequency (the upper threshold of the 95% CI of 4/91084 alleles) of the c.572G>A variant in DCLRE1C is 0.00001425 for South Asian chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting. However, 2 homozygous individuals have been reported in the Middle Eastern population: 18/6062 alleles, freq: 0.002969. Therefore, PM2 is not applicable, and BS2 is met at the Supporting level (BS2_Supporting). The Middle Eastern population: 18/6062 alleles, freq: 0.002969, meet the BS1 threshold (>0.00078), so BS1 is met. To our knowledge, this variant has not been reported in the literature in individuals affected with SCID/DCLRE1C-related conditions or in functional studies. In summary, this variant meets the criteria to be classified as Likely Benign for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: BS2_Supporting and BS1 (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001215552	SCV001387303	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2023-12-11	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 191 of the DCLRE1C protein (p.Arg191Gln). This variant is present in population databases (rs528699445, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 945025). 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 with a negative predictive value of 80%. 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.
Natera, Inc.	RCV001828716	SCV002084836	uncertain significance	Athabaskan severe combined immunodeficiency	2021-01-07	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004758148	SCV005348696	likely benign	DCLRE1C-related disorder	2024-06-07	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).