NM_001283009.2(RTEL1):c.3730T>C (p.Cys1244Arg) AND Inborn genetic diseases

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003258663.9

Allele description [Variation Report for NM_001283009.2(RTEL1):c.3730T>C (p.Cys1244Arg)]

NM_001283009.2(RTEL1):c.3730T>C (p.Cys1244Arg)

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_001283009.2(RTEL1):c.3730T>C (p.Cys1244Arg)

HGVS:

NC_000020.11:g.63695558T>C
NG_033901.1:g.42749T>C
NG_046961.1:g.3908T>C
NM_001283009.2:c.3730T>CMANE SELECT
NM_001283010.1:c.2983+78T>C
NM_016434.4:c.3652+78T>C
NM_032957.5:c.3724+78T>C
NP_001269938.1:p.Cys1244Arg
NP_001269938.1:p.Cys1244Arg
LRG_1149t1:c.3724+78T>C
LRG_1149t2:c.3730T>C
LRG_1149t3:c.3652+78T>C
LRG_1149:g.42749T>C
LRG_1149p2:p.Cys1244Arg
NC_000020.10:g.62326911T>C
NM_001283009.1:c.3730T>C
NM_032957.4:c.3724+78T>C
NR_037882.1:n.4557T>C

Protein change:

C1244R; CYS1244ARG

Links:

OMIM: 608833.0008; dbSNP: rs587777037

NCBI 1000 Genomes Browser:

rs587777037

Molecular consequence:

NM_001283010.1:c.2983+78T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_016434.4:c.3652+78T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_032957.5:c.3724+78T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001283009.2:c.3730T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_037882.1:n.4557T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Inborn genetic diseases
Identifiers:: MeSH: D030342; MedGen: C0950123

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003945155	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (May 22, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23591994, 30088779 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003945155

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(May 22, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Human RTEL1 deficiency causes Hoyeraal-Hreidarsson syndrome with short telomeres and genome instability.

Le Guen T, Jullien L, Touzot F, Schertzer M, Gaillard L, Perderiset M, Carpentier W, Nitschke P, Picard C, Couillault G, Soulier J, Fischer A, Callebaut I, Jabado N, Londono-Vallejo A, de Villartay JP, Revy P.

Hum Mol Genet. 2013 Aug 15;22(16):3239-49. doi: 10.1093/hmg/ddt178. Epub 2013 Apr 15.

PubMed [citation]

PMID:: 23591994

Impaired Cytomegalovirus Immunity in Idiopathic Pulmonary Fibrosis Lung Transplant Recipients with Short Telomeres.

Popescu I, Mannem H, Winters SA, Hoji A, Silveira F, McNally E, Pipeling MR, Lendermon EA, Morrell MR, Pilewski JM, Hanumanthu VS, Zhang Y, Gulati S, Shah PD, Iasella CJ, Ensor CR, Armanios M, McDyer JF.

Am J Respir Crit Care Med. 2019 Feb 1;199(3):362-376. doi: 10.1164/rccm.201805-0825OC.

PubMed [citation]

PMID:: 30088779
PMCID:: PMC6363970

Details of each submission

From Ambry Genetics, SCV003945155.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.3724+78T>C intronic alteration results from a T to C substitution 78 nucleotides after coding exon 33 of the RTEL1 gene._x000D_ _x000D_ _x000D_ _x000D_ The c.3730T>C (p.C1244R) alteration is located in exon 34 (coding exon 33) of the RTEL1 gene. This alteration results from a T to C substitution at nucleotide position 3730, causing the cysteine (C) at amino acid position 1244 to be replaced by an arginine (R). Based on data from gnomAD, the C allele has an overall frequency of 0.002% (5/247318) total alleles studied. The highest observed frequency was 0.005% (1/18282) of East Asian alleles. This variant was detected in two affected siblings with shortened telomere length and abnormal telomere function. Both of these siblings were compound heterozygous carriers of this variant as well as RTEL1 c.2097C>G (p.I699M) (Le Guen, 2013). This variant has also been detected in heterozygous form in a 61 year old female with idiopathic pulmonary fibrosis post lung transplant who also had severely shortened telomeres (Popescu, 2019). This nucleotide position is highly conserved in available vertebrate species._x000D_ _x000D_ Leave out nucleotide conservation sentence and table? The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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