Submissions for variant NM_001033855.3(DCLRE1C):c.106A>G (p.Lys36Glu)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV003072019	SCV004810402	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-03-08	reviewed by expert panel	curation	The c.106A>G(NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Lysine by Glutamic Acid at amino acid 36 (p.Lys36Glu). The filtering allele frequency (the upper threshold of the 95% CI of 41/1179924) of the c.106A>G variant in DCLRE1C is 0.00002626 for European (non-Finnish) 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 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	RCV003072019	SCV003460359	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamic acid at codon 36 of the DCLRE1C protein (p.Lys36Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals 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.