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NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His) AND Dyskeratosis congenita

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Sep 20, 2019
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000586517.15

Allele description [Variation Report for NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His)]

NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His)

Genes:
RTEL1-TNFRSF6B:RTEL1-TNFRSF6B readthrough (NMD candidate) [Gene - HGNC]
RTEL1:regulator of telomere elongation helicase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
20q13.33
Genomic location:
Preferred name:
NM_001283009.1(RTEL1):c.3791G>A (p.Arg1264His)
Other names:
uc021wge.1:c.3791G>A; NM_001283009.1:p.Arg1264His; p.Arg1010Ter
HGVS:
  • NC_000020.11:g.63695619G>A
  • NG_033901.1:g.42810G>A
  • NG_046961.1:g.3969G>A
  • NM_001283009.2:c.3791G>AMANE SELECT
  • NM_001283010.1:c.2983+139G>A
  • NM_016434.4:c.3652+139G>A
  • NM_032957.5:c.3724+139G>A
  • NP_001269938.1:p.Arg1264His
  • NP_001269938.1:p.Arg1264His
  • LRG_1149t1:c.3724+139G>A
  • LRG_1149t2:c.3791G>A
  • LRG_1149t3:c.3652+139G>A
  • LRG_1149:g.42810G>A
  • LRG_1149p2:p.Arg1264His
  • NC_000020.10:g.62326972G>A
  • NM_001283009.1:c.3791G>A
  • NM_001283009.2:c.3791G>A
  • NM_032957.4:c.3724+139G>A
  • NM_032957.5:c.3724+139G>A
  • NR_037882.1:n.4618G>A
  • p.Arg1264His
Protein change:
R1264H; ARG1264HIS
Links:
Counsyl: 143983; OMIM: 608833.0002; dbSNP: rs201540674
NCBI 1000 Genomes Browser:
rs201540674
Molecular consequence:
  • NM_001283010.1:c.2983+139G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_016434.4:c.3652+139G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_032957.5:c.3724+139G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001283009.2:c.3791G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_037882.1:n.4618G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Dyskeratosis congenita
Identifiers:
MONDO: MONDO:0015780; MedGen: C0265965; OMIM: PS127550

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000699754Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Sep 20, 2019) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001365991Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Likely pathogenic
(May 3, 2019) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001456933Natera, Inc.
no assertion criteria provided
Pathogenic
(Sep 16, 2020) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown11not providednot providednot providedclinical testing

Citations

PubMed

A homozygous mutation of RTEL1 in a child presenting with an apparently isolated natural killer cell deficiency.

Hanna S, Béziat V, Jouanguy E, Casanova JL, Etzioni A.

J Allergy Clin Immunol. 2015 Oct;136(4):1113-4. doi: 10.1016/j.jaci.2015.04.021. Epub 2015 May 27. No abstract available.

PubMed [citation]
PMID:
26025130

Constitutional mutations in RTEL1 cause severe dyskeratosis congenita.

Walne AJ, Vulliamy T, Kirwan M, Plagnol V, Dokal I.

Am J Hum Genet. 2013 Mar 7;92(3):448-53. doi: 10.1016/j.ajhg.2013.02.001. Epub 2013 Feb 28.

PubMed [citation]
PMID:
23453664
PMCID:
PMC3591859
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000699754.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365991.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not provided1not provided

From Natera, Inc., SCV001456933.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024