NM_001283009.2(RTEL1):c.1940C>T (p.Pro647Leu) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 20, 2022
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:: RCV000695530.7

Allele description [Variation Report for NM_001283009.2(RTEL1):c.1940C>T (p.Pro647Leu)]

NM_001283009.2(RTEL1):c.1940C>T (p.Pro647Leu)

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.1940C>T (p.Pro647Leu)

Other names:

p.Pro647Leu

HGVS:

NC_000020.11:g.63689563C>T
NG_033901.1:g.36754C>T
NM_001283009.2:c.1940C>TMANE SELECT
NM_001283010.1:c.1271C>T
NM_016434.4:c.1940C>T
NM_032957.5:c.2012C>T
NP_001269938.1:p.Pro647Leu
NP_001269939.1:p.Pro424Leu
NP_057518.1:p.Pro647Leu
NP_116575.3:p.Pro671Leu
NP_116575.3:p.Pro671Leu
LRG_1149t1:c.2012C>T
LRG_1149t2:c.1940C>T
LRG_1149t3:c.1940C>T
LRG_1149:g.36754C>T
LRG_1149p1:p.Pro671Leu
LRG_1149p2:p.Pro647Leu
LRG_1149p3:p.Pro647Leu
NC_000020.10:g.62320916C>T
NM_032957.4:c.2012C>T
NR_037882.1:n.2767C>T

Protein change:

P424L

Links:

dbSNP: rs1177091623

NCBI 1000 Genomes Browser:

rs1177091623

Molecular consequence:

NM_001283009.2:c.1940C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001283010.1:c.1271C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_016434.4:c.1940C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_032957.5:c.2012C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_037882.1:n.2767C>T - 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
SCV000824036	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25848748, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824036

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 20, 2022)

germline

clinical testing

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

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

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

Stuart BD, Choi J, Zaidi S, Xing C, Holohan B, Chen R, Choi M, Dharwadkar P, Torres F, Girod CE, Weissler J, Fitzgerald J, Kershaw C, Klesney-Tait J, Mageto Y, Shay JW, Ji W, Bilguvar K, Mane S, Lifton RP, Garcia CK.

Nat Genet. 2015 May;47(5):512-7. doi: 10.1038/ng.3278. Epub 2015 Apr 13.

PubMed [citation]

PMID:: 25848748
PMCID:: PMC4414891

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824036.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 647 of the RTEL1 protein (p.Pro647Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with a personal and family history of pulmonary fibrosis (PMID: 25848748). ClinVar contains an entry for this variant (Variation ID: 553611). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.

#	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: Sep 29, 2024

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