Submissions for variant NM_001033855.3(DCLRE1C):c.632G>C (p.Gly211Ala)

gnomAD frequency: 0.00002  dbSNP: rs1056674146

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001224711	SCV004810432	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2024-03-08	reviewed by expert panel	curation	The c.632G>C (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause the substitution of Glycine by Alanine at amino acid 211 (p.Gly211Ala). The filtering allele frequency (the upper threshold of the 95% CI) of the c.632G>C variant in DCLRE1C is 0.00001921 African/African American Genomes, 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 v4. One patient is reported in the literature (PMID: 34420125) present: *Diagnostic criteria for SCID/Leaky SCID/Omenn syndrome met 0.5pt + *SCID gene panel or exome/genome sequencing conducted 0.5pt + *T-B-NK+ lymphocyte subset profile 0.5 pt, total is 1.5pts. PP4_Supporting. This proband is compound heterozygous for mutations in DCLRE1C, with a maternally inherited pathogenic deletion in exons 1–3 (at least LP according to SCID VCEP specifications) and a paternally variant (NM 001033855.2; c.632G > C, p.Gly211Ala). 1 point, PM3 is met. 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, PP4_Supporting, and PM3_Moderate (VCEP specifications version 1).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001224711	SCV001396927	uncertain significance	Severe combined immunodeficiency due to DCLRE1C deficiency	2021-08-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with alanine at codon 211 of the DCLRE1C protein (p.Gly211Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of severe combined immunodeficiency (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. 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.