Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000669062 | SCV000793763 | uncertain significance | Dyskeratosis congenita, autosomal recessive 5 | 2017-08-30 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001217029 | SCV001388856 | uncertain significance | Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 | 2024-12-24 | criteria provided, single submitter | clinical testing | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 964 of the RTEL1 protein (p.Phe964Leu). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RTEL-1 related conditions and/or Hoyeraal-Hreidarsson syndrome (PMID: 23453664, 26022962, 28495692, 29296694, 30995915). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Phe988Leu. ClinVar contains an entry for this variant (Variation ID: 553584). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323669 | SCV004029759 | pathogenic | Dyskeratosis congenita | 2023-07-27 | criteria provided, single submitter | clinical testing | Variant summary: RTEL1 c.2964T>G (p.Phe988Leu) results in a non-conservative amino acid change located in the Regulator of telomere elongation helicase 1 (IPR030845) of the encoded protein sequence. This variant is also known as c.2892T>G (p.Phe964Leu). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249372 control chromosomes (gnomAD). c.2964T>G has been reported in the literature in individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) with evidence of cosegregation with disease (Walne_2013). The variant was also found in individuals reported to have features of the disease, including aplastic anemia and pulmonary fibrosis (Arias-Salgado_2019, Galvez_2021, Touzot_2016). Another nucleotide alteration (c.2962T>C) resulting in the same misense change has been found in association with interstitial lung disease (HGMD, Kannengiesser_2015). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 23453664, 26022962, 33718801, 30995915, 29296694). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Prevention |
RCV004535683 | SCV004118711 | likely pathogenic | RTEL1-related disorder | 2022-08-30 | criteria provided, single submitter | clinical testing | The RTEL1 c.2964T>G variant is predicted to result in the amino acid substitution p.Phe988Leu. This variant was reported in the homozygous state in two siblings with dyskeratosis congenita and one patient with inherited bone marrow failure syndrome (Walne et al 2013. PubMed ID: 23453664; Table S5, Gálvez et al 2021. PubMed ID: 33718801). In the heterozygous state this variant has been reported in two siblings with pulmonary fibrosis (described as p.Phe964Leu, Kannengiesser et al 2015. PubMed ID: 26022962). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating it is rare. This variant is interpreted as likely pathogenic. |
| Baylor Genetics | RCV000669062 | SCV004209331 | likely pathogenic | Dyskeratosis congenita, autosomal recessive 5 | 2023-10-23 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV001217029 | SCV005663951 | pathogenic | Dyskeratosis congenita, autosomal recessive 5; Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 | 2024-04-22 | criteria provided, single submitter | clinical testing |