NM_001283009.2(RTEL1):c.751G>A (p.Glu251Lys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 30, 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:: RCV002513344.3

Allele description [Variation Report for NM_001283009.2(RTEL1):c.751G>A (p.Glu251Lys)]

NM_001283009.2(RTEL1):c.751G>A (p.Glu251Lys)

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.751G>A (p.Glu251Lys)

HGVS:

NC_000020.11:g.63672607G>A
NG_033901.1:g.19798G>A
NM_001283009.2:c.751G>AMANE SELECT
NM_001283010.1:c.82G>A
NM_016434.4:c.751G>A
NM_032957.5:c.823G>A
NP_001269938.1:p.Glu251Lys
NP_001269939.1:p.Glu28Lys
NP_057518.1:p.Glu251Lys
NP_116575.3:p.Glu275Lys
NP_116575.3:p.Glu275Lys
LRG_1149t1:c.823G>A
LRG_1149t2:c.751G>A
LRG_1149t3:c.751G>A
LRG_1149:g.19798G>A
LRG_1149p1:p.Glu275Lys
LRG_1149p2:p.Glu251Lys
LRG_1149p3:p.Glu251Lys
NC_000020.10:g.62303960G>A
NM_032957.4:c.823G>A
NR_037882.1:n.1578G>A

Protein change:

E251K; GLU275LYS

Links:

OMIM: 608833.0006; dbSNP: rs398123019

NCBI 1000 Genomes Browser:

rs398123019

Molecular consequence:

NM_001283009.2:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001283010.1:c.82G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_016434.4:c.751G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032957.5:c.823G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_037882.1:n.1578G>A - 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
SCV003443827	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23453664, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003443827

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 30, 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

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

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, SCV003443827.1

#	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 glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 251 of the RTEL1 protein (p.Glu251Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dyskeratosis congenita (PMID: 23453664). This variant is also known as p.Gly275Lys. ClinVar contains an entry for this variant (Variation ID: 42022). 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 (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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: Oct 8, 2024

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