Submissions for variant NM_001033855.3(DCLRE1C):c.262G>A (p.Glu88Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV002659719	SCV004810408	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-02-15	reviewed by expert panel	curation	The c.262G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glutamic Acid by Lysine at amino acid 88 p.Glu88Lys. The filtering allele frequency (the upper threshold of the 95% CI of 90/1164454) of the c.262G>A variant in DCLRE1C is 0.00006702 for European (non-Finnish) chromosomes by gnomAD v4, which is lower than the SCID-VCEP threshold for BS1 (>0.00078) and BA1 (>0.00346) but higher than the threshold (<0.00003266) for PM2_Supporting (BS1 not met, BA1 not met, PM2_Supporting not met). No homozygotes have been observed in gnomAD v4. To our knowledge, this variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions or in functional studies. Due to insufficient evidence, this variant is 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 (specification version 1.0): No criteria were applied.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002659719	SCV003519079	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2022-03-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 88 of the DCLRE1C protein (p.Glu88Lys). This variant is present in population databases (rs753976764, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DCLRE1C-related conditions. 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: "Tolerated"; 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.