Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001248679 | SCV005375418 | uncertain significance | Severe combined immunodeficiency due to DCLRE1C deficiency | 2024-06-13 | reviewed by expert panel | curation | The c.550A>T (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Cysteine at amino acid 184 (p.Ser184Cys). The filtering allele frequency (the upper threshold of the 95% CI of 23/44878 alleles) of the c.550A>T variant in DCLRE1C is 0.0003498 for East Asian 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). There is one homozygous occurrence in gnomAD v4, BS2_Supporting. 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: BS2_Supporting (VCEP specifications version 1). |
Illumina Laboratory Services, |
RCV000401504 | SCV000361559 | uncertain significance | Histiocytic medullary reticulosis | 2018-01-12 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
Labcorp Genetics |
RCV001248679 | SCV001422184 | uncertain significance | Severe combined immunodeficiency due to DCLRE1C deficiency | 2022-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 184 of the DCLRE1C protein (p.Ser184Cys). This variant is present in population databases (rs373675907, gnomAD 0.04%). 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: 299320). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 | RCV004021468 | SCV004853509 | uncertain significance | Inborn genetic diseases | 2021-09-14 | criteria provided, single submitter | clinical testing | The c.550A>T (p.S184C) alteration is located in exon 8 (coding exon 8) of the DCLRE1C gene. This alteration results from a A to T substitution at nucleotide position 550, causing the serine (S) at amino acid position 184 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |