ClinVar Miner

Submissions for variant NM_001033855.3(DCLRE1C):c.1903dup (p.Ser635fs)

dbSNP: rs760288938
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530013 SCV000645223 likely benign Severe combined immunodeficiency due to DCLRE1C deficiency 2024-01-25 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000779020 SCV000915464 uncertain significance Histiocytic medullary reticulosis 2017-08-31 criteria provided, single submitter clinical testing The DCLRE1C c.1903dupA (p.Ser635LysfsTer6) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant has not therefore been reported in the literature in association with Omenn syndrome. The p.Ser635LysfsTer6 variant is reported at a frequency of 0.002465 in the Ashkenazi Jewish population from the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Based on the potential impact of frameshift variants and the lack of clarifying evidence, the p.Ser635LysfsTer6 variant is classified as a variant of unknown significance but suspicious for pathogenicity for Omenn syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV001280949 SCV001468303 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency; Histiocytic medullary reticulosis 2021-03-30 criteria provided, single submitter clinical testing DCLRE1C NM_001033855.2 exon 14 p.Ser635Lysfs*6 (c.1903dupA): This variant has been reported in the literature in 1 individual with breast cancer (Lhota 2016 PMID:26822949). This variant is present in 0.2% (24/10360) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/10-14950582-C-CT?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:468484). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a duplication of 1 nucleotide at position 1903. This variant creates a premature stop codon 6 amino acids downstream from this location which results in an absent or abnormal protein. However, this variant occurs within the last exon of this gene; due to its position, it is possible that this protein may escape nonsense mediated decay. Variants occuring in this region have been reported to retain high activity levels potentially consistent with a less severe phenotype (Felgentreff 2016 PMID: 25917813). Further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Genome-Nilou Lab RCV000530013 SCV001653465 uncertain significance Severe combined immunodeficiency due to DCLRE1C deficiency 2021-05-18 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001507776 SCV001713537 uncertain significance not provided 2020-08-13 criteria provided, single submitter clinical testing
GeneDx RCV001507776 SCV001780435 uncertain significance not provided 2019-11-18 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation as the last 58 amino acids are lost and replaced with 5 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Observed previously in one patient with breast cancer (Lhota et al., 2016); This variant is associated with the following publications: (PMID: 33206719, 26822949)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222547 SCV002500467 uncertain significance not specified 2022-03-18 criteria provided, single submitter clinical testing Variant summary: DCLRE1C c.1903dupA (p.Ser635LysfsX6) results in a premature termination codon located in exon 14 (i.e. in the last exon), therefore it is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a C-terminal portion of the 692 amino acid long protein. One truncation downstream of this position has been reported in a homozygous individual affected with primary immunodeficiency (PMID: 32888943, through HGMD), however no further evidence details (e.g. phenotype severity) were provided on this case. The variant allele was found at a frequency of 0.0004 in 251198 control chromosomes, predominantly within the Ashkenazi Jewish and South Asian subpopulations with frequencies of 0.0024 and 0.001, respectively, in the gnomAD database (v2.1, exomes dataset). The observed variant frequencies within the Ashkenazi Jewish and South Asian control individuals are approximately 3.4 and 1.4 fold higher (respectively) than the estimated maximal expected allele frequency (MPAF) for a pathogenic variant in DCLRE1C causing Severe Combined Immunodeficiency phenotype (0.00071), suggesting that the variant is a benign polymorphism. In addition, the variant was also reported in the Turkish population in individuals undergoing whole exome- or genome sequencing, who had unrelated phenotypes to the variant, with a frequency of 0.0019, which is about 2.7 fold higher than the MPAF. To our knowledge, no occurrence of c.1903dupA in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. An in vitro functional study examined several truncations upstream from our variant, and found that they retained relatively high residual activity levels (50-98%), however, no clear correlation was observed with the level of residual activity and the position of the truncations, therefore it is not possible to make clear conclusions about the variant effect for a truncation located a downstream from the examined variants. Authors of this study also noted that the observed hypomorphic effect for C-terminal truncations was consistent with a less severe phenotype in several reported cases who had these variants in homozygous state (PMID: 25917813). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as likely benign (n=1) and VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.

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