chr20-63693160-C-T

Variant names:

• chr20-63693160-C-T
• rs398123018
• NM_001283009.2:c.2869C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_Moderate PP5

The NM_001283009.2(RTEL1):​c.2869C>T​(p.Arg957Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000428 in 1,612,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R957P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: RTEL1 NM_001283009.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:3
• Conservation: PhyloP100: 5.34
• Publications: 14 publications found

Genes affected

RTEL1 (HGNC:15888): (regulator of telomere elongation helicase 1) This gene encodes a DNA helicase which functions in the stability, protection and elongation of telomeres and interacts with proteins in the shelterin complex known to protect telomeres during DNA replication. Mutations in this gene have been associated with dyskeratosis congenita and Hoyerall-Hreidarsson syndrome. Read-through transcription of this gene into the neighboring downstream gene, which encodes tumor necrosis factor receptor superfamily, member 6b, generates a non-coding transcript. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2013]

RTEL1-TNFRSF6B (HGNC:44095): (RTEL1-TNFRSF6B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring RTEL1 (regulator of telomere elongation helicase 1) and TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy) genes on chromosome 20. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 20-63693160-C-T is Pathogenic according to our data. Variant chr20-63693160-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42021.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001283009.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	NM_001283009.2	MANE Select	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	NP_001269938.1
	RTEL1	NM_032957.5		c.2941C>T	p.Arg981Trp	missense	Exon 30 of 35	NP_116575.3
	RTEL1	NM_016434.4		c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	NP_057518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RTEL1	ENST00000360203.11	TSL:5 MANE Select	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	ENSP00000353332.5
	RTEL1	ENST00000508582.7	TSL:2	c.2941C>T	p.Arg981Trp	missense	Exon 30 of 35	ENSP00000424307.2
	RTEL1	ENST00000370018.7	TSL:1	c.2869C>T	p.Arg957Trp	missense	Exon 30 of 35	ENSP00000359035.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000401 AC: 10 AN: 249160 AF XY: 0.0000517

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1459956 Hom.: 0 Cov.: 33 AF XY: 0.0000358 AC XY: 26 AN XY: 726274

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52070

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000459 AC: 51 AN: 1111574

Other (OTH) AF: 0.0000829 AC: 5 AN: 60330

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74282

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000497 AC: 6

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dyskeratosis congenita, autosomal recessive 5 Pathogenic:3

Mar 14, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 07, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Dyskeratosis congenita Pathogenic:2

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 11, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RTEL1 c.2941C>T (p.Arg981Trp), also reported as p.R734W and p.R957W, results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 4e-05 in 249160 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RTEL1 causing Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) (4e-05 vs 0.0011), allowing no conclusion about variant significance. c.2941C>T has been observed in the compound heterozygous and homozygous states in multiple individual(s) affected with clinical features and/or diagnosis of Dyskeratosis Congenita (Hoyeraal Hreidarsson Syndrome) (example, Walne_2013, Touzot_2016). It has also been observed in the heterozygous state in multiple individuals with and without family history of pulmonary fibrosis (example, Borie_2019, Fang_2020). These data indicate that the variant is likely to be associated with disease. Multiple reports provide experimental evidence that this variant is associated with reduced DNA replication fork function/partner protein interaction in vitro and decreased telomere length in vivo (example, Walne_2013, Takedachi_2020, Touzot_2016). The following publications have been ascertained in the context of this evaluation (PMID: 23829372, 23453664, 24582487, 30523160, 32583532, 39279213, 32398829, 29296694). ClinVar contains an entry for this variant (Variation ID: 42021). Based on the evidence outlined above, the variant was classified as likely pathogenic.

not provided Pathogenic:1 Uncertain:1

Dec 01, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in the heterozygous state in unrelated patients with pulmonary fibrosis in published literature (PMID: 30523160, 32583532); Published functional studies demonstrate telomere shortening, increased T-circle formation, and replication fork stalling (PMID: 23453664, 29296694, 32398829); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as R957W and R734W; This variant is associated with the following publications: (PMID: 30523160, 34183866, 27415407, 28714244, 25940403, 23453664, 32583532, 29296694, 28099038, 24582487, 32398829)

Sep 27, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Pathogenic:1 Uncertain:1

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal dominant dyskeratosis congenita 4 and autosomal recessive dyskeratosis congenita 5 (MIM#615190), and autosomal dominant pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 3 (MIM#616373). (I) 0108 - This gene is associated with both recessive and dominant disease. Currently, the genotype-phenotype relationship has not been established (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Monoallelic pathogenic variants have been reported in asymptomatic family members (PMID: 23329068, 25848748, 35199181). (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4: 69 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v4) (highest allele count: 31 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Two alternative changes, p.(Arg947Gln) and p.(Arg957Pro), have been classified as VUS by clinical laboratories in ClinVar. p.(Arg957Gln) was also observed in a large chronic hypersensitivity pneumonitis cohort (PMID: 31268371). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic by five clinical laboratories and as a VUS by two clinical laboratories in ClinVar. It has been reported in three compound heterozygous families and one homozygous individual with features consistent with autosomal recessive dyskeratosis congenita (PMIDs: 23453664, 29296694). This variant has also been identified in individuals with idiopathic pulmonary fibrosis and interstitial lung disease and has been classified as a VUS and pathogenic (personal communication, PMIDs: 30523160, 32583532). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jul 19, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset and therefore considered benign. Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042021). This variant has been reported to be associated with both dykeratosis congenita (PMID: 29296694) and pulmonary fibrosis (PMID: 30523160). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

RTEL1-related disorder Pathogenic:1

Jan 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The RTEL1 c.2941C>T variant is predicted to result in the amino acid substitution p.Arg981Trp. This variant has been reported in the compound heterozygous state with a second RTEL1 variant in three unrelated patients with autosomal recessive dyskeratosis congenita (DC) and segregated with DC in all the families (Walne et al 2013. PubMed ID: 23453664). Functional studies of patient cells showed significant defects in telomere maintenance (Walne et al 2013. PubMed ID: 23453664). This variant has also been reported in the heterozygous state in three members from one family affected with autosomal dominant pulmonary fibrosis (PF) and segregated with PF in this family (referred to as p.Arg957Trp, Borie R et al 2019. PubMed ID: 30523160). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD. Together we classify the c.2941C>T variant as likely pathogenic.

Dyskeratosis congenita, autosomal recessive 5;C4225346:Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 957 of the RTEL1 protein (p.Arg957Trp). This variant is present in population databases (rs398123018, gnomAD 0.01%). This missense change has been observed in individuals with dyskeratosis congenita (PMID: 23453664). This variant is also known as c.2941C>T (p.Arg981Trp). ClinVar contains an entry for this variant (Variation ID: 42021). 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.57		Loss of disorder (P = 0.0476)
MVP		0.73
ClinPred		0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.74
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123018; hg19: chr20-62324513; COSMIC: COSV58890761; COSMIC: COSV58890761;