ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.281C>A (p.Ser94Tyr)

gnomAD frequency: 0.00003  dbSNP: rs762266339
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV002554997 SCV004810411 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2024-02-15 reviewed by expert panel curation The c.281C>A (NM_001033855.3) variant in DCLRE1C is a missense variant predicted to cause substitution of Serine by Tyrosine at amino acid 94 (p.Ser94Tyr). The filtering allele frequency (the upper threshold of the 95% CI of 20/1097996 alleles) of the c.281C>A variant in DCLRE1C is 0.00001189 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. 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: PM2_Supporting (specification version 1.0).
Illumina Laboratory Services, Illumina RCV001102650 SCV001259335 uncertain significance Histiocytic medullary reticulosis 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV002554997 SCV003276574 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2022-03-15 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 94 of the DCLRE1C protein (p.Ser94Tyr). This variant is present in population databases (rs762266339, gnomAD 0.007%). 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: 877154). 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.

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