Submissions for variant NM_001033855.3(DCLRE1C):c.1991G>A (p.Arg664Gln)

gnomAD frequency: 0.00004  dbSNP: rs779159378

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000810272	SCV004810437	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-03-08	reviewed by expert panel	curation	NM_001033855.3(DCLRE1C):c.1991G>A is a missense variant predicted to cause substitution of Arginine by Glutamine at amino acid 664 (p.Arg664Gln). The filtering allele frequency (the upper threshold of the 95% CI of 4/59972) of the c.1991G>A variant in DCLRE1C is 0.00002985 for Admixed American chromosomes by gnomAD v4, which is lower than the ClinGen SCID VCEP threshold (<0.00003266) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). No homozygotes have been observed in gnomAD. 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 a variant of uncertain significance for autosomal recessive severe combined immunodeficiency due to DCLRE1C deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP: PM2_Supporting (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810272	SCV000950465	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-08-08	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 664 of the DCLRE1C protein (p.Arg664Gln). This variant is present in population databases (rs779159378, gnomAD 0.03%). 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: 654335). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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.
Ambry Genetics	RCV002537327	SCV003757954	likely benign	Inborn genetic diseases	2022-01-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000810272	SCV005912782	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2021-11-12	criteria provided, single submitter	research
Natera, Inc.	RCV001272771	SCV001455071	uncertain significance	Histiocytic medullary reticulosis	2020-09-16	no assertion criteria provided	clinical testing