Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001247262 | SCV004810428 | uncertain significance | Severe combined immunodeficiency due to DCLRE1C deficiency | 2024-04-01 | reviewed by expert panel | curation | The c.590G>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Asparagine at amino acid 197 (p.Ser197Asn). The filtering allele frequency (the upper threshold of the 95% CI of 95/1180058 alleles) of the c.590G>A variant in DCLRE1C is 0.00006723 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. Another missense variant [c.589A>G (p.Ser197Gly)] in the same codon has been reported; However, this variant was classified as VUS by the ClinGen SCID VCEP (PM5 not 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 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 |
RCV001247262 | SCV001420671 | uncertain significance | Severe combined immunodeficiency due to DCLRE1C deficiency | 2022-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 197 of the DCLRE1C protein (p.Ser197Asn). This variant is present in population databases (rs773799685, gnomAD 0.01%). 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: 971474). 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. 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. |
Al Jalila Children’s Genomics Center, |
RCV001247262 | SCV001984062 | uncertain significance | Severe combined immunodeficiency due to DCLRE1C deficiency | 2021-03-22 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002564119 | SCV003750264 | uncertain significance | Inborn genetic diseases | 2022-08-16 | criteria provided, single submitter | clinical testing | The c.590G>A (p.S197N) alteration is located in exon 8 (coding exon 8) of the DCLRE1C gene. This alteration results from a G to A substitution at nucleotide position 590, causing the serine (S) at amino acid position 197 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Natera, |
RCV001835293 | SCV002079191 | uncertain significance | Athabaskan severe combined immunodeficiency | 2020-08-07 | no assertion criteria provided | clinical testing |