ClinVar Miner

Submissions for variant NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His) (rs201540674)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Center for Mendelian Genomics, University of Washington RCV000201662 SCV000256245 pathogenic Idiopathic Pulmonary Fibrosis 2015-05-19 criteria provided, single submitter research
Counsyl RCV000034860 SCV000485950 likely pathogenic Dyskeratosis congenita, autosomal recessive, 5 2016-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000524079 SCV000617167 pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing The R1264H variant in the RTEL1 gene has been reported previously in the homozygous and compound heterozygous states in individuals with Hoyeraal Hreidarsson syndrome (Ballew et al., 2013; Walne et al., 2013; Hanna et al., 2015). The R1264H variant is suggested to be a common founder mutation in the Ashkenazi Jewish population, with a 1% carrier rate in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish populations (Fedick et al., 2014). The R1264H variant is a conservative amino acid substitution, which occurs at a position within the C4C4 domain described by Sarek et al. that is not conserved across species (2015). However, functional studies indicate that R1264H leads to a significant increase in telomere loss and an increase in cells with telomere dysfunction-induced foci (Sarek et al., 2015). We interpret R1264H as a pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586517 SCV000699754 pathogenic Dyskeratosis congenita 2019-09-20 criteria provided, single submitter clinical testing 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.
Invitae RCV000814441 SCV000954851 pathogenic Dyskeratosis congenita, autosomal recessive, 5; Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1264 of the RTEL1 protein (p.Arg1264His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201540674, ExAC 0.01%). This variant has been observed in several individuals and families affected with RTEL1-related conditions, and has been reported as a potential Ashkenazi Jewish founder mutation (PMID: 25047097, 23453664, 24009516, 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). Experimental studies have shown that this sequence change results in increased telomere loss and dysfunction (PMID: 24009516, 25620558). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000586517 SCV001365991 likely pathogenic Dyskeratosis congenita 2019-05-03 criteria provided, single submitter clinical testing 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 (, 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.
OMIM RCV000034860 SCV000058464 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2015-03-15 no assertion criteria provided literature only
OMIM RCV000201217 SCV000255953 pathogenic Pulmonary fibrosis and/or bone marrow failure, telomere-related, 3 2015-03-15 no assertion criteria provided literature only
GeneReviews RCV000034860 SCV000282030 pathogenic Dyskeratosis congenita, autosomal recessive, 5 2016-05-26 no assertion criteria provided literature only
Natera, Inc. RCV000586517 SCV001456933 pathogenic Dyskeratosis congenita 2020-09-16 no assertion criteria provided clinical testing

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