NM_001283009.2(RTEL1):c.3715_3716del (p.Ala1240fs) AND multiple conditions

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 14, 2023
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:: RCV000812646.7

Allele description [Variation Report for NM_001283009.2(RTEL1):c.3715_3716del (p.Ala1240fs)]

NM_001283009.2(RTEL1):c.3715_3716del (p.Ala1240fs)

Genes:

RTEL1-TNFRSF6B:RTEL1-TNFRSF6B readthrough (NMD candidate) [Gene - HGNC]
RTEL1:regulator of telomere elongation helicase 1 [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

20q13.33

Genomic location:

Preferred name:

NM_001283009.2(RTEL1):c.3715_3716del (p.Ala1240fs)

HGVS:

NC_000020.11:g.63695541TC[1]
NG_033901.1:g.42732TC[1]
NG_046961.1:g.3891TC[1]
NM_001283009.2:c.3715_3716delMANE SELECT
NM_001283010.1:c.2983+63_2983+64del
NM_016434.4:c.3652+63_3652+64del
NM_032957.5:c.3724+63_3724+64del
NP_001269938.1:p.Ala1240fs
LRG_1149t1:c.3724+63_3724+64del
LRG_1149t2:c.3715_3716del
LRG_1149t3:c.3652+63_3652+64del
LRG_1149:g.42732TC[1]
LRG_1149p2:p.Ala1240fs
NC_000020.10:g.62326893_62326894del
NC_000020.10:g.62326894TC[1]
NM_001283009.1:c.3715_3716del
NR_037882.1:n.4540TC[1]

Protein change:

A1240fs

Links:

dbSNP: rs1363658406

NCBI 1000 Genomes Browser:

rs1363658406

Molecular consequence:

NM_001283009.2:c.3715_3716del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001283010.1:c.2983+63_2983+64del - intron variant - [Sequence Ontology: SO:0001627]
NM_016434.4:c.3652+63_3652+64del - intron variant - [Sequence Ontology: SO:0001627]
NM_032957.5:c.3724+63_3724+64del - intron variant - [Sequence Ontology: SO:0001627]
NR_037882.1:n.4540TC[1] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Dyskeratosis congenita, autosomal recessive 5 (DKCB5)
Identifiers:: MONDO: MONDO:0014076; MedGen: C3554656; OMIM: 615190

Name:: Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3
Synonyms:: PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 3
Identifiers:: MONDO: MONDO:0014613; MedGen: C4225346; Orphanet: 2032; OMIM: 616373

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000952966	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 14, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23453664, 24009516, 25047097, 25099625, 25620558, 26025130, 28492532
SCV002811747	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000952966

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 14, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV002811747

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 4, 2022)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

A recessive founder mutation in regulator of telomere elongation helicase 1, RTEL1, underlies severe immunodeficiency and features of Hoyeraal Hreidarsson syndrome.

Ballew BJ, Joseph V, De S, Sarek G, Vannier JB, Stracker T, Schrader KA, Small TN, O'Reilly R, Manschreck C, Harlan Fleischut MM, Zhang L, Sullivan J, Stratton K, Yeager M, Jacobs K, Giri N, Alter BP, Boland J, Burdett L, Offit K, Boulton SJ, et al.

PLoS Genet. 2013 Aug;9(8):e1003695. doi: 10.1371/journal.pgen.1003695. Epub 2013 Aug 29.

PubMed [citation]

PMID:: 24009516
PMCID:: PMC3757051

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000952966.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RTEL1 protein in which other variant(s) (p.Arg1264) have been determined to be pathogenic (PMID: 23453664, 24009516, 25047097, 25099625, 25620558, 26025130). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 656263). This variant has not been reported in the literature in individuals affected with RTEL1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Ala1240Argfs*21) in the RTEL1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the RTEL1 protein. The RTEL1 gene has multiple clinically relevant transcripts. This variant occurs in alternate transcript NM_001283009.1, and corresponds to NM_032957.4:c.3724+63_3724+64delTC in the primary transcript.

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002811747.1

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

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

Last Updated: Sep 29, 2024

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