ClinVar Genomic variation as it relates to human health

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1264 of the RTEL1 protein (p.Arg1264His). This variant is present in population databases (rs201540674, gnomAD 0.3%). This missense change has been observed in individuals with RTEL1-related conditions (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 23453664, 24009516, 25047097, 25099625, 26025130). This variant is also known as c.3724+139G>A on transcript NM_032957.4. ClinVar contains an entry for this variant (Variation ID: 42018). 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. Experimental studies have shown that this missense change affects RTEL1 function (PMID: 24009516, 25620558). For these reasons, this variant has been classified as Pathogenic.

The p.Arg1264His variant in RTEL1 has been reported in the homozygous state in 4 individuals with Dyskeratosis Congenita (DC) or Hoyeraal Hreidarsson (HH), a severe form of DC (Ballwe 2013, Gueye 2014, Hanna 2015). It has also been identified in the compound heterozygous state with another missense variant in an individual with HH (Walne 2013). In addition, this variant was identified in the heterozygous state in 2 siblings with pulmonary fibrosis (Cogan 2015). Although some variants in RTEL1 have been reported to be associated with increased risk for developing pulmonary fibrosis or other isolated features of DC, additional evidence would be needed to determine if this variant confers a risk for disease in the heterozgous state. This variant has also been identified in 0.35% (36/10234) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org), and a carrier screening study identified the variant in 1% of the orthodox Ashkenazi Jewish population and 0.45% of the general Ashkenazi Jewish population (Fedick 2015). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein; however, in vitro functional studies suggest that this variant impacts protein function (Sarek 2015). In summary, although the allele frequency of this variant in the Ashkenazi Jewish population of gnomAD is higher than the expected maximum allele frequency for a pathogenic variant in RTEL1, this variant meets criteria to be classified as likely pathogenic for autosomal recessive dyskeratosis congenita. ACMG/AMP Criteria applied: PM3_Strong, PS3_Moderate, PP4, BS1.

The c.3724+139G>A alteration consists of a G to A substitution 139 nucleotides after exon 34 (coding exon 33) in the NM_032957 isoform of the RTEL1 gene. This alteration is also referred to as c.3791G>A (p.R1264H), which is located in exon 34 (coding exon 33) in the NM_001283009 isoform of the RTEL1 gene, and results from a G to A substitution at nucleotide position 3791, causing the arginine (A) at amino acid position 1264 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD) database, the RTEL1 c.3724+139G>A alteration was observed in 0.01% (41/278700) of total alleles studied, with a frequency of 0.35% (36/10234) in the Ashkenazi Jewish subpopulation. This alteration has been reported in the homozygous and compound heterozygous states in patients with Hoyeraal-Hreidarsson syndrome and/or immunodeficiency. Heterozygous carriers in these families were reportedly unaffected (Ballew, 2013; Walne, 2013; Hanna, 2015). This alteration has an estimated carrier frequency of 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population (Fedick, 2015). This alteration has also been identified in the heterozygous state in two siblings with adult-onset pulmonary fibrosis (Cogan, 2015). Patient-derived cell lines demonstrated deficient function as indicated by telomere length heterogeneity, the presence of extra-chromosomal circular telomeric DNA, hypersensitivity to DNA damage and increased sister chromatid exchange (Ballew, 2013). In addition, both patient-derived cells and mutant mouse embryonic fibroblasts demonstrated compromised RTEL1-TRF2 interaction leading to accumulation of telomere circles and telomere loss (Sarek, 2015). Based on the available evidence, this alteration is classified as likely pathogenic.

Variant summary:RTEL1 NM_032957.4:c.3724+139G>A, also known as c.3791G>A (p.Arg1264His) in NM_001283009.1 (rs201540674), is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Arg1264 is highly conserved and is centrally located within the putative C4C4 Zn2+ coordination domain of the encoded protein. In silico prediction algorithms (SIFT, PolyPhen-2, and Condel) indicate that this amino acid substitution is likely to be damaging to the protein (Ballew_2013). The variant allele was found at a frequency of 0.00016 in 247320 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RTEL1 causing Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) (0.00016 vs 0.0011), allowing no conclusion about variant significance. c.3724+139G>A has been reported in the literature in multiple individuals affected with Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome)(Walne_2013, Ballew_2013) including at-least one ascertained report of its homozygous presence in an individual with isolated natural killer cell deficiency (Hanna_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in telomere dysfunction, including significantly decreased telomere length, telomere length heterogeneity, and the presence of extra-chromosomal circular telomeric DNA. In addition, RTEL1 mutant cells exhibited enhanced sensitivity to the interstrand cross-linking agent mitomycin C (Ballew_2013). Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All clinical diagnostic laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

ACMG categories: PS3,PM3,PP3,PP5,BP1

Published functional studies demonstrate a significant increase in telomere loss and increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015); Observed in the heterozygous state in individuals reported to be clinically unaffected, as well as individuals with a history of pulmonary fibrosis or myelodysplastic syndrome in individuals referred for genetic testing at GeneDx and in published literature (Ballew et al., 2013; Walne et al., 2013; Cogan et al., 2015; Hanna et al., 2015); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 30088779, 23453664, 25047097, 24009516, 25607374, 26025130, 28507545, 27415407, 32135276, 32710398, 34021146, 32561545, 28104920, 25099625, 34308104, 25620558)